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Title: Structural Classification and Comparative Analysis of Terpenoids: Focus on Sesquiterpenoids and Triterpenoids
Structural Classification and Skeletal Diversity of Sesquiterpenoids and Triterpenoids
Isoprene Unit-Based Structural Classification and Skeletal Diversity of Sesquiterpenoids and Triterpenoids
Sesquiterpenoids (C15, Three Isoprene Units)
Sesquiterpenoids exhibit extensive structural diversity across natural sources, with their biosynthesis rooted in farnesyl pyrophosphate (FPP) cyclization, followed by rearrangements or eliminations to form diverse carbon frameworks [1]. Their classification includes acyclic, monocyclic, bicyclic, and tricyclic types [1], with KEGG further categorizing them into acyclic, bisabolene-type, germacrene-type, humulene-type, and cadinyl-type [2].
Biosynthetic studies highlight the role of sesquiterpene synthases: AcTPS3 catalyzes FPP cyclization to cubenene (with minor products α-muurolene and epicubebol) [3], while TEAS uses (cis,trans)-FPP to form the (6S)-α-bisabolyl cation, which yields products like (+)-2-epi-prezizaene and (-)-α-cedrene via conformational isomerization [4]. A total of 28 TPS genes related to sesquiterpene synthesis (e.g., gemmarane, guaiane synthases) have been annotated [5].
Natural sources span plants, fungi, algae, sponges, and soft corals, with structural determination via NMR and X-ray analysis [6]. Examples include novel rearranged cadinane-type (cinnamoids A, D) and cadin-2(3)-en-5-one derivatives (cinnamoids B, C) [7], omphalic acid and omphalane-skeleton compounds [8], and agarofuran sesquiterpenoids in Celastraceae [9]. Sesquiterpenoid lactones are prevalent in Podanthus species [9] and Lychnophorinae (35 identified) [10], with some (e.g., in TMHM) having bitter taste and allergy-inducing properties [11].
Key sources and their sesquiterpenoid profiles include:
- G. guidonia volatile oil: Eudesmane/guaiane-skeleton compounds (e.g., eudesma-5,7-diene, guai-6-en-10β-ol) [12]
- T. speciosa aerial parts: Acyclic-farnesane, caryophyllane, eudesmane classes (isoalantolactone, alantolactone) [13]
- A. sinensis tissues: 43 sesquiterpenes across 11 classes (eremophilane, prezizaane) [5]
- V. jatamansi essential oil: 64.2% sesquiterpenoids (patchoul, α-bulnesene) [14]
- C. camphora chemotypes: Longifolene, bicyclogermacrene [15]
- P. sylvestris: trans-β-caryophyllene, cis-α-bisabolene (78% of SQT fraction) [16]
- Curcuma species: 382 sesquiterpenes (bisabolane/guaiane types dominant) [17]
Synthetic approaches have constructed trans-fused skeletons (trans-marasmane, trans-illudane) from a bicyclic cycloenone intermediate [18]. Sesquiterpenoids also function as pheromones: (6R,7S)-himachala-9,11-diene in flea beetles [19], γ-cadinene/γ-cadinenal in Reticulitermes flavipes [19], and (E,E)-α-farnesene in Ceratitis capitata [19].
Triterpenoids (C30, Six Isoprene Units)
Triterpenoids are derived from 2,3-oxidosqualene (MVA pathway), with structural diversity driven by oxidosqualene cyclases (OSCs) and modifying enzymes (P450s, UGTs) [20]. Most are tetracyclic (lanostane-type) or pentacyclic (ursane, oleanane, lupane) [1], with steroids as modified triterpenoids [21].
Biosynthetic OSCs are divided into P-group (tetracyclic cycloartenol via chair-boat-chair) and D-group (pentacyclic lupeol/β-amyrin via chair-chair-chair) [22]. Key sources include plants (cuticles, cell walls), basidiomycete mushrooms (fruit bodies, mycelium), photosynthetic bacteria, and invertebrates [23].
Structural diversity is exemplified by:
- Limonoids (Meliaceae): Tetranortriterpenoids (evodulone, mexicanolide) [24]
- Ganoderma triterpenoids: Lanostane-type (ganoderic acids, lucidenic acids) [739, 1044]
- Ziziphus triterpenoids: Lupane (betulinic acid), ceanothane, ursane, oleanane, and dammarane types (jujubosides) [25]
- Cimicifugae Rhizoma: 211 cycloartane triterpenoid saponins (cimigenol-type dominant) [26]
Pharmacological activities include anticancer effects (artemisinin derivatives via iron-mediated peroxide cleavage [27]; celastrol, cucurbitacins targeting cell cycle/apoptosis [27]), anti-inflammatory properties (Commiphora wightii triterpenoids [28]), and antiviral activity (ursolic acid inhibiting adenovirus [29]).
Key sources and their triterpenoid profiles include:
- Eucalyptus outer bark: Ursolic acid (most abundant), betulinic/oleanolic acids [30]
- Lingonberry fruit wax: Ursane-, oleanane-, lupane-type triterpenoids (α/β-amyrins, lupeol) [31]
- I. obliquus sclerotia: Lanostane-type (inotodiol) and pentacyclic (betulin) triterpenoids [32]
- E. dendroides latex: 79.53% triterpenoids (cycloartenol, cycloeucalenol) [33]
- Yellow Cuban propolis: Type A (cycloartenol, lupeol, β-amyrin; 6.8–21.4 μg/100 μg extract) and Type B (lupeol acetate, β-amyrin acetate; 2.4–12.8 μg/100 μg extract) [34]
Triterpenoids also form self-assemblies: betulinic acid gels in 19 organic liquids [35], while dihydroxy triterpenoids form nano/micrometer flowers [35]. Their fragmentation patterns (RDA reactions, neutral losses of H2O/CO2) aid identification via mass spectrometry [955, 1087].
Comparative Overview of Sesquiterpenoid and Triterpenoid Diversity
| Feature | Sesquiterpenoids (C15) | Triterpenoids (C30) |
|---|---|---|
| Precursor | Farnesyl pyrophosphate (FPP) [1] | 2,3-Oxidosqualene (MVA pathway) [20] |
| Key Synthases | Sesquiterpene synthases (AcTPS3, TEAS) [489, 559]; 28 TPS genes [5] | Oxidosqualene cyclases (P/D groups) [22]; β-amyrin/lupeol synthases [36] |
| Major Skeletons | Eudesmane, guaiane, cadinane, acyclic-farnesane [455, 474, 573] | Ursane, oleanane, lupane, lanostane, dammarane [739, 1009] |
| Representative Compounds | Artemisinin, β-caryophyllene, isoalantolactone [950, 474, 1088] | Ursolic acid, betulinic acid, ganoderic acid [1088, 1009, 739] |
| Biosynthetic Modifications | Wagner–Meerwein rearrangement, methyl group displacement [1] | P450 oxidation, glycosylation, acylation [20] |
| Natural Sources | Plants, fungi, algae, sponges, soft corals [6] | Plants, basidiomycetes, bacteria, invertebrates [23] |
| Key Biological Roles | Pheromones (flea beetles, termites) [19]; anticancer (artemisinin) [27] | Anticancer (betulinic acid, celastrol) [1013, 950]; anti-inflammatory [28] |
Source-Specific Distribution and Quantitative Profiling of Sesquiterpenoids and Triterpenoids
Sesquiterpenoids and triterpenoids exhibit broad distribution across plant species, with their presence, profiles, and abundances varying by source, extraction method, and environmental factors. Phytochemical screening confirms terpenoids (including sesquiterpenoids and triterpenoids) in diverse plant extracts, while quantitative and qualitative analyses reveal specific constituents, concentration shifts, and structural diversity.
Distribution, Abundance, and Constituents of Sesquiterpenoids and Triterpenoids Across Sources
| Source | Terpenoid Class | Key Details | Citations |
|---|---|---|---|
| Solenostemon monostachyus extracts | Terpenoids (sesquiterpenoids, triterpenoids) | Detected via phytochemical screening | [37] |
| Aqueous extracts of unspecified plants | Terpenoids (sesquiterpenoids, triterpenoids) | Detected via phytochemical screening | [38] |
| L. europaeum | Terpenoids (sesquiterpenoids, triterpenoids) | Detected via phytochemical screening | [39] |
| Leaf extracts of antibacterial agent source | Terpenoids (sesquiterpenoids, triterpenoids) | Detected via phytochemical screening | [40] |
| C. timoriensis flower non-aqueous extracts (hexane, ethanol, methanol) | Terpenoids (sesquiterpenoids, triterpenoids), steroids | Contains β-sitosterol, stigmasterol (anti-inflammatory potential) | [41] |
| Aqueous extract (unspecified plant) | Triterpenoids (ursolic acid), general terpenoid fraction | Ursolic acid: 17.82% of total compounds; general terpenoid fraction: 4.35% | [42] |
| Unspecified plant (CAM I sample) | Volatile sesquiterpenoids | 11 terpenoids among 77 volatile compounds; dendrolasin (major marker): 75.09% | [43] |
| Cretaceous French ambers | Sesquiterpenoids (dihydrocadinene, 5,6,7,8-tetrahydrocadalene, cadala-1(10),3,8-triene, α-calacorene), diagenetic products | Diagenetic products (ionene, methyl-ionene) universally present | [44] |
| Guggul resin | Sesquiterpenoids, triterpenoids, monoterpenoids, diterpenoids | Detected alongside other terpenoid classes | [45] |
| Unspecified plant (steaming treatment) | Sesquiterpenes (α-humulene, β-caryophyllene, guaia-6,9-diene, α-selinene) | α-humulene: 4.62% (untreated) → 7.01% (20s steaming); β-caryophyllene: 21.04% → 28.47%; guaia-6,9-diene/α-selinene induced post-treatment | [46] |
| Unspecified plant extracts | Sesquiterpenes (calamenene, cadalene), triterpenes (β-sitosterol) | Detected via identification | [47] |
| H. italicum essential oil (EO) | Sesquiterpenoids | Highest sesquiterpenoid level (15%); hydrocarbon sesquiterpenes more abundant than oxygenated forms | [48] |
| Unspecified EO | Sesquiterpenoids (44.20% total: 24.80% hydrocarbons, 19.40% oxygenated) | Main constituents: β-bourbonene, intermedeol, muurola-4,10(14)-dien-1-ol | [49] |
| Lavender EOs | Sesquiterpenes (α-muurolol, caryophyllene oxide, γ-cadinene) | α-muurolol: 10.36–19.67%; caryophyllene oxide: 5.50–9.08%; γ-cadinene: 4.43–8.66%; supplementary irrigation/oven drying alter levels | [50] |
| Old sample (unspecified plant) | Monoterpenoids, sesquiterpenoids | Several compounds diminished or absent | [51] |
| R. uniflorum | Sesquiterpenoids (12 isolated; 8 new to species) | Leaves: highest content (19.85 mg/g) with cynaropicrin (6), aguerin B (3); guaiane content varies by season/location | [52] |
| R. raetam stem extract | Sesquiterpenoids | Appreciable amount detected | [53] |
| F. hispida | Sesquiterpenoids, triterpenoids (15 isolated: ursolic acid 2, oleanolic acid-28-O-α-D-glucopyranoside 3, etc.) | Rich terpenoid source | [54] |
| Pigeon pea leaf EO (SFME vs. HD) | Sesquiterpenes (72.89% SFME, 65.26% HD) | Key constituents: α-copaene (5.89±0.16% SFME, 4.83±0.17% HD), β-caryophyllene (7.46±0.19% SFME, 5.89±0.16% HD), etc. | [55] |
| L. cajanderi trees | Sesquiterpenoids (1–3% of VOC emissions) | Dominated by farnesene/alloaromadrendrene (over half), β-caryophyllene (17–29%); increases end of summer (one tree) | [56] |
| Brugmansia suaveolens | Sesquiterpenoids (3) | Detected alongside other secondary metabolites | [57] |
| S. calyculata SFME oil | Sesquiterpenes, nonterpenoids | Rich in both classes | [58] |
| Nemania aquilariae | Sesquiterpenoids | All 5 volatile components identified | [59] |
| Cannabis | Sesquiterpenoids (β-caryophyllene, α-humulene, β-farnesene, γ-eudesmol) | Linear increase with PPFD; variable across sampling weeks | [60] |
| Unspecified analysis | Sesquiterpenoids (49), triterpenoids (10) | 3 triterpenoids in positive ion mode; additional in anion mode | [61] |
| Unspecified plant (stems, leaves, flowers, stamens) | Sesquiterpene hydrocarbons | Stems: 38.4% (humulene 15.2%); leaves: 77.5% (β-caryophyllene 36.7%, (E,E)-α-farnesene 38.3%); flowers: 62.2–77.9%; stamens: 72.5% | [62] |
| Unspecified plant volatile oil | Sesquiterpenes (bicyclogermacrene 20.4%, spathulenol 3.1%, etc.) | Detected via analysis | [63] |
| L. indica | Sesquiterpene lactones (little lactucin, 8-desoyllactucin, lactucopicrin) | Lactucin: 1.9–98.7 μg/g (mean 25.7 μg/g) at flowering stage (61 accessions) | [64] |
| Citrus flavedo hexanic extracts (HFV, HFN) | Triterpenic compounds | 5.2% (HFV), 7.6% (HFN) of total components | [65] |
| Citrus albedo hexanic extracts (HAN, HAV) | Triterpenoids | 1.3% (HAN), 0.8% (HAV) of total components | [65] |
| Citrus hexanic extracts (high molecular weight section) | Triterpenoids (β-sitosterol acetate, β-sitosterol, stigmastan-3-5-diene, β-tocopherol) | Identified via chromatography | [65] |
| Citrus methanolic extracts (albedo: MAN, MAV; flavedo: MFN, MFV) | Triterpenoids (β-sitosterol) | Detected in extracts | [65] |
| Silybum marianum achenes | Triterpenoids | Small amount present | [66] |
| Clerodendrum genus | Triterpenoids, sesquiterpenes | Yielded alongside other compounds | [67] |
| Taraxacum mongolicum Hand.-Mazz. (TMHM) | Triterpenoids (pentacyclic: taraxerol, φ-taraxasterol, etc.), sesquiterpene lactones (over 15) | Isolated from species | [11] |
| Dracocephalum moldavica L. aerial parts | Triterpenoids (5) | Yielded from aerial parts | [68] |
| A. galangal, C. longa, Z. officinale crude extracts | Triterpenoids | Detected via phytochemical screening | [69] |
| C. spinosum (Sicily vs. Crete) | Sesquiterpene lactones | Sicily: lactucin, 11β,13-dihydroderivative, leucodin, tanacetin; Crete: lactucopicrin, 3,4β-dihydroderivative | [70] |
| FAG samples | Terpenoids (6 sesquiterpenes, 11 triterpenes) | 24 terpenoid compounds assigned | [71] |
| C. tomentosum leaf extract | Terpenoids, triterpenes | Yielded from extract | [72] |
| Reissantia indica, Cissus cornifolia, Grosseria vignei | Terpenoids, triterpenoids | Detected via analysis | [73] |
| Unspecified plant alcoholic leaf extract | Terpenoids | Tested positive | [74] |
| V. variabilis leaf resin | Terpenes | Positive Liebermann-Burchard’s test | [75] |
| PPE | Triterpenoids | Detected via phytochemical screening | [76] |
| E. tirucalli latex | C-30 triterpenoids | Reported composition | [77] |
| Marsegu wood | Triterpenoids | Detected via identification | [78] |
| Croton zehntneri Pax & K. Hoffm. leaves | Monoterpenoids, sesquiterpenoids | Present in essential oils | [79] |
| Neoboutonia macrocalyx Pax stem barks | Cycloartane triterpenes (neomacrolactone, 22α-acetoxyneomacrolactone, etc.) | Isolated from stem barks | [79] |
| Uapaca nitida Müll-Arg. root barks | Betulinic acid | Contains triterpenoid | [79] |
| Uapaca paludosa Aubrév. & Landri trunk barks | Squalene, betulinic acid, betulin, samvisterin | Contains triterpenoids | [79] |
| Terpiospora speciosa aerial parts | Sesquiterpenoids (64.7% of oil: acyclic-farnesane 26.2%, caryophyllane 11.6%, eudesmane 14.5%) | Isoalantolactone (3.1%), alantolactone (4.1%) present | [13] |
| Artemisia californica leaf tissue | Sesquiterpenes (17) | Population differences in concentration/composition; α-bisabolol/unknown terpene F drive dissimilarity | [80] |
| Spruce genotypes | Sesquiterpenes | Genotype 1: α-farnesene, β-farnesene, α-bisabolene; Genotype 2: only (E)-β-farnesene | [81] |
| Eugenia species | Cyclic sesquiterpenes (EOs), triterpenoids (pentacyclic: betulinic acid, α/β-amirins) | Sesquiterpenes main volatile class; triterpenoids isolated from stems/leaves | [82] |
| Unspecified EO | Sesquiterpenes (78.26%: β-caryophyllene oxide 33.97%, modephene 23.34%), triterpenoids | Triterpenoids <2% | [83] |
| Pummelos | Sesquiterpenoids (14: acyclic, bisabolene-type, germacrene-type, humulene-type, cadinyl-type) | Acyclic/cadinyl-type higher in one variety; germacrene/humulene-type lower | [2] |
| Bitumen samples (saturated fractions) | Sesquiterpenoids (nordrimane, elemane, etc.), non-hopanoid triterpenoids (des-A-olean-13(18)-ene, etc.) | Low quantities | [84] |
| Bitumen samples (aromatic fractions) | Sesquiterpenoids (dihydro-ar-curcumene, gamma-cadinene, etc.), non-hopanoid triterpenoids (ring-A-monoaromatic, etc.) | Cadalene predominant (sesquiterpenoids); 24,25-dinoroleana-1,3,5(10),12-tetraene/24,25-dinorlupa-1,3,5(10)-triene predominant (triterpenoids) | [84] |
| Chloranthaceae species (22) | Terpenoids (682 total: 275 sesquiterpenoids) | Sesquiterpenoids main structural type; dimeric lindenane sesquiterpenoids most frequent | [85] |
| E. dendroides latex | Sesquiterpenes (3.75%: b-cedrene most abundant), triterpenes (79.53%: cycloartenol 21.36%, etc.) | Triterpenes largest compound class | [33] |
| Curcuma species | Mono-, sesquiterpenoids (bisabolane-type, germacerene isomeric), triterpenoids | 250+ terpenoids; 382 sesquiterpenes across 28 species; bisabolane/guaiane types dominant; hop-17(21)-en-3β-ol, etc., isolated from C. longa | [1061, 1076] |
| Bryophytes | Triterpenoids (mosses/hornworts), mono-/di-/sesquiterpenoids (liverworts, oil bodies) | 9 triterpenoids detected in genuine mosses | [86] |
| Ageratum nudiflora leaf unsaponifiable fractions | Triterpenoids (β-amyrin 7.1%, α-amyrin 2.8%, lupeol 2.6%, uvaol 1.6%, etc.) | Identified post-fractionation | [87] |
| Mentha officinalis, Sideritis fruticosa, Salvia species | Triterpenoids (ursolic, oleanolic acids), diterpenoids | Present in extracts | [88] |
| Stem bark ethanol extracts, EBHA-Janaúba/S.Bu subextratos, unspecified sample | Triterpenoids | Detected via phytochemical screening; one sample lacks steroids | [639, 648, 650] |
| Ramaria brevipes sporocarps (uninfected vs. infected) | Sesquiterpenoids, triterpenoids | Present in uninfected; absent in infected | [89] |
| Endophytes (2) | Triterpenoids | Detected via thin layer chromatography | [90] |
| Uvariodendron anisatum root powder/extracts | Terpenoids (triterpenoids) | Positive Salkowski's test | [91] |
| Unspecified plant (bark, leaf, seed extracts) | Triterpenes | Bark: 4; leaf:7; seed:5 | [92] |
| D. digyna leaves (spring) | Unidentified triterpenes (2) | Significantly higher levels than other seasons | [93] |
| Selected plant extracts | Triterpenoids | Detected via phytochemical screening | [94] |
| Plantaginis Semen | Triterpenoids (sumaresinol, oleanolic acid, ursonic acid, oleanolic acid acetate) | 4 triterpenoids characterized | [95] |
| Unspecified sample (polar fraction) | Triterpenoids (33.6% of total wax: pentacyclic triterpene alcohol/ketone 32.2%) | Urs-12-en-28-al, 6a,14a-methanopicene, β-amyrin (14.2% of total wax) | [96] |
| Baizongia/Geoica galls | Triterpenoids | Most abundant terpenoid class; Baizongia galls highest concentration | [97] |
| B. dracunculifolia organic extracts | Triterpenoids | Rich source | [98] |
| I. obliquus extracts | Phytosterols, triterpenoids (ergosterol, lanosterol, inotodiol, trametenolic acid, betulin) | Dominant constituents | [99] |
| Psidium species | Ursane-type pentacyclic triterpenes | Most reported triterpenes | [100] |
| Edible fungi (mushrooms) | Triterpenoids | Wide array present | [101] |
| Neem (kernel vs. pericarps) | C-seco triterpenoids (kernel: azadirachtin, salannin, etc.), ring-intact triterpenoids (pericarps: azadirone, etc.) | C-seco major in kernel/stem/bark; ring-intact major in pericarp/flower/leaf | [102] |
| Neem (AiSQS enzyme) | Triterpenoids | 5x higher expression in fruit vs. leaves; 10x higher vs. flowers (correlates with profiling) | [102] |
| AC products | Triterpenoids | Natural fruiting bodies (A–D) higher than cultivated (G–I); none in fermented broth (I) | [103] |
| Bitumen samples (alicyclic HCs) | Triterpenes (taraxerene, neohop-13(18)-ene, diploptene) | Highest concentrations among alicyclic HCs | [104] |
| Swertia species | Triterpenoids (oleanolic acid, ursolic acid), steroidal framework terpenoids (≈40) | Isolated from species | [105] |
| Ganoderma species (G. mastoporum, G. lucidum, etc.) | Lanostane-type triterpenoids (ganomastenols, ganoderic acids, etc.) | Multiple compounds isolated; G. lucidum total triterpenoids 10x higher than G. sinense | [106] |
| Panax ginseng | Glycosylated triterpenoids (ginsenosides: PPD-, PPT-, OCT-, OA-type) | Major bioactive constituents | [107] |
| Various plants/fungi | Triterpenoids (ursolic acid, betulinic acid, glycyrrhizic acid, etc.) | Widely distributed natural compounds | [107] |
Sesquiterpenes, formed by three isoprene units, exhibit structural diversity (acyclic, monocyclic, bicyclic, tricyclic) with hydrocarbon and oxygenated derivatives [108]. In some oil headspaces, sesquiterpene hydrocarbons (17.7–62.1%) and oxygenated sesquiterpenes (0.7–3.1%) co-occur with non-terpene derivatives and minor monoterpenes [108]. During fruit maturation, sesquiterpene hydrocarbons follow a decrease-then-increase trend (e.g., α-copaene 9.0–43.3%), while (E,E)-α-farnesene increases then declines; oxygenated sesquiterpenes remain constant before a final sharp decline [108].
Triterpenoids, derived from squalene (30-carbon intermediate) or (E,E,E)-geranylgeranyl diphosphate (GGPP), include over 18,000 compounds across 126+ carbon skeletons [798, 1088]. They show distinct distribution: liverworts store smaller terpenoids in oil bodies, while mosses/hornworts produce triterpenoids [86]. Triterpenoids are often extracted from plant resin/sap and include pentacyclic forms (e.g., betulinic acid, α/β-amyrins) and glycosylated variants (e.g., ginsenosides) [684, 1088].
Across studies, terpenoids (17%) are among the most frequently isolated compound classes, alongside flavonoids (28%), alkaloids (14%), and others [109]. Environmental and processing factors—such as steaming, irrigation, drying methods, geographic location, and cultivation status—consistently alter terpenoid profiles and abundances, highlighting their dynamic nature in biological systems.
Isolation, Structural Elucidation Methods, and Subclass-Specific Characteristics of Sesquiterpenoids and Triterpenoids
Terpenoids are biosynthetically derived from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via the mevalonic acid (MVA) or 2-C-methylerythritol phosphate (MEP) pathways, and are classified by isoprene units into subclasses including sesquiterpenoids (C15) and triterpenoids (C30) [110]. Below is a consolidated summary of their structural diversity, isolation methods, and bioactivities:
Sesquiterpenoid and Triterpenoid Structural Diversity, Isolation, and Bioactivities
| Class | Skeleton/Subtype | Examples | Source/Context | Citations |
|---|---|---|---|---|
| Sesquiterpenoids | Bergamotane, bisabolane, drimane, humulane-derived, eremophilane, cadinene, eudesmane | 81 sesquiterpenoids from Aspergillus species | Skeletal diversity in fungi | [110] |
| Aromadendrane | 4α,10β-aromadendranediol, 4β,10α-aromadendranediol | Structural examples | [111][112] | |
| Guaiane | 4β,10α-dihydroxy-guai-6-ene, 4β,6β,7β,10α-tetrahydroxy-guaiane | Structural examples; anti-Trypanosoma cruzi activity (EC50 16.3–17.6 μM) | [111][113] | |
| Muurolane | Tsarvanin A (2,9-dihydroxymuurol-3(4)-en-12-oic acid derivative) | Isolated from A. sieversiana areolas | [114] | |
| Isodaucane, oppositane | — | Additional skeletons | [115] | |
| Caryophyllene, copaene | — | CRM1 (sesquiterpenoid-rich fraction) 11x more active than oil-resin | [116] | |
| Dihydro-β-agarofuran | — | Substrates of P-gp; MDR modulators; weak cytotoxicity (IC50 30.2 µM) against HeLa | [117] | |
| KEGG classification | Acyclic (farnesol, nerolidol), bisabolene-type, germacrene-type (germacrene B/D, nootkatone), humulene-type (caryophyllene), cadinyl-type (δ-cadinene) | Classification system examples | [2] | |
| γ-lactone/ketone moieties | C15H20O3 (γ-lactone + ketone), C15H22O3 (γ-lactone + hydroxyl) | Isolated from hexane:benzene fractions | [118] | |
| Sesquiterpene lactones | Lactucin, 11β,13-dihydroderivative, leucodin, tanacetin | Isolated from C. spinosum | [70] | |
| Oplopane-type | — | Main component of Tussilago farfara (FF); structural changes at positions 1,7,14 | [119] | |
| Bisabolene-type | — | Main component of FF; oxidation at positions 1,5,8 | [119] | |
| Eudesmane-type | 6β,14-epoxyeudesm-4(15)-en-1β-ol, 11-methoxyopposit-4(15)-en-1β-ol, 10β-hydroxycadin-4-en-15-al | Isolated from various plant sources | [120] | |
| Other components | Spatulenol, β-caryophyllene, caryophyllene oxide, α-eudesmol | Identified in S. terebinthifolia | [121] | |
| Copaenol | — | First identification from Lantana genus | [122] | |
| Triterpenoids | 30-norlanostane | Nidulanosides A/B (C9 side chain at C-17, C3-C19 hemi-acetal) | Novel structures from Aspergillus | [110] |
| Lanostane | Asperfumins A/B; ganoderic acids (e.g., 11α-hydroxy-3,7-dioxo-5α-lanosta-8,24(E)-dien-26-oic acid); ganoderiols; ganolucidic acids; lucidenic acids | Isolated from Ganoderma species (e.g., G. lucidum, G. tsugae, G. applanatum, G. pfeifferi) | [110][123][106] | |
| Lupan/oleanane | Betulinic acid, α/β-amirins | From Eugenia species; oleanane-type is predominant in Tripterygium | [82][117] | |
| Ursane | Euscaphic acid, 1β-hydroxyeuscaphic acid, hyptatic acid B, 19α-hydroxyasiatic acid, trachelosperogenin, 4-epi-nigaichigoside F1, nigaichigoside F1, trachelosperoside B-1 | Characteristic of Rubus genus (e.g., R. rosifolius fruits) | [124][125] | |
| Friedelane | Celastrol (anticancer, insulin resistance relief) | Active ingredient in Tripterygium; linked to autoimmune disease treatment | [117] | |
| Taraxerane | Taraxerol, φ-taraxasterol, taraxasterol | Isolated from TMHM | [11] | |
| Cycloartane | Schipropins A–J (C-3/C-4 cleavage) | Isolated from S. propinqua | [126] | |
| C-seco | Azadirachtin, salannin, nimbin | Kernel-specific in Neem | [102] | |
| Ring-intact | Azadirone, azadiradione, epoxyazadiradione, gedunin | Pericarp/flower/leaf-specific in Neem | [102] | |
| Other components | β-amyrin, erythrodiol, oleanolic acid, ursolic acid, lupeol, uvaol, hederagenin, bayogenin acid | Isolated from various plant sources (e.g., S. terebinthifolia, Lantana species) | [87][127][121][122] | |
| Saponins | Gymnemasins A–D (G. sylvestre leaves); glycyrrhizic acid (detoxification, anti-inflammatory) | Glycyrrhizic acid identified via [M-H]- at m/z 821.3958; fragment ions from glucuronide loss | [128][129][130] | |
| Isolation Methods | Solvent extraction | Alcoholic/acetonic extracts + liquid/liquid partition; petroleum ether/CHCl3; Soxhlet (hexane) | Used for O. sessiliflora branches, olive-oil wastes, Curcuma wenyujin (MSPD) | [131][117][132][133] |
| Chromatography | Column chromatography (silica gel, HP-20, C18), HPLC, MPLC, flash chromatography, HSCCC, UFLC-MSn | Purified sesquiterpenoids/triterpenoids from A. sieversiana, G. lucidum, C. macrophyllus | [111][114][123][134][135] | |
| Pre-fractionation/PTLC | Silica columns + silver nitrate PTLC | Isolation of sesquiterpenoids | [134] | |
| Analysis techniques | GLC, GC-MS, UHPLC-HRMS, NMR, MS, SC-XRD, CD calculations | Used for identification in Tragopogon species, Pseudobombax ellipticum, M. horridula | [124][126][136][137][138] | |
| Bioactivities | Sesquiterpenoids | Anti-T. cruzi (guaiane-type), MDR modulation (dihydro-β-agarofuran), anti-inflammatory (C. rotundus components), bitter taste/allergy (TMHM lactones) | Various therapeutic and toxic effects | [111][117][11][134] |
| Triterpenoids | Anti-inflammatory (pachymic acid, ursolic acid IC50 17 μM), anticancer (celastrol, ganoderic acid X), cytotoxicity (G. sylvestre saponins), detoxification (glycyrrhizic acid) | Wide range of pharmacological activities | [131][117][128][106][130] |
Sesquiterpenoids exhibit extensive skeletal diversity, with examples spanning fungi (e.g., Aspergillus [110]) and plants (e.g., C. spinosum [70], T. farfara [119]). Triterpenoids, while less abundant in some fungal sources, include novel structures like nidulanosides A/B [110] and species-specific skeletons (e.g., 19-α-hydroxyursane in Rubus [125], friedelane in Tripterygium [117]). Isolation typically involves solvent extraction (e.g., alcoholic/acetonic extracts [131]) and chromatographic fractionation (e.g., HPLC [114]), with structural elucidation relying on NMR (1D/2D [111][114]), MS (HRESIMS [124]), and SC-XRD (absolute configurations [114][139]). Bioactivities are subclass-specific: guaiane-type sesquiterpenoids show anti-T. cruzi activity [111], while triterpenoids like celastrol and glycyrrhizic acid exhibit anticancer and anti-inflammatory effects, respectively [117][130]. Tissue-specific accumulation (e.g., Neem kernels [102]) and geographic variation (e.g., R. uniflorum leaves [52]) further highlight the complexity of terpenoid biology.
Comparative Analysis of Biosynthetic Pathways and Enzymatic Regulation for Sesquiterpenoid and Triterpenoid Production
Terpenoids are classified by the number of isoprene units into subgroups including sesquiterpenoids (C15) and triterpenoids (C30) [140]. Sesquiterpenoids, the largest subgroup of terpenoids, are present in essential plant oils, seaweed/algae, and fungi, with applications as biofuels (e.g., β-bisabolene, β-caryophyllene), antiviral agents, and anti-inflammatory compounds [140]. Triterpenoids, among the most structurally diverse specialized metabolites across taxa, include compounds like ginsenosides, ursolic acid, and sterols, with uses in pharmaceutical, cosmetic, and food industries [140][20][22].
Key Characteristics of Sesquiterpenoids and Triterpenoids
| Feature | Sesquiterpenoids | Triterpenoids |
|---|---|---|
| Isoprene units/C atoms | 3 / C15 [141] | 6 / C30 [141] |
| Number of characterized structures | Over 7000 (sesquiterpene lactones most frequent in natural remedies) [141] | Over 23000 (largest group in terpenoid family) [142] |
| Direct precursor | Farnesyl diphosphate (FPP) [142] | 2,3-Oxidosqualene [20][22] |
| Core biosynthetic enzyme | Sesquiterpene synthases (STSs) [143] | Oxidosqualene cyclases (OSCs) [20][22] |
| Cyclization mechanism | Cyclization of FPP via carbocation intermediates (class I enzymes) [140] | Cyclization of 2,3-oxidosqualene via protonation/epoxidation (class II enzymes) [140] |
| Typical structures | Mono-, bi-, or tricyclic compounds [141] | Complex cyclic structures (tetracyclic: 6-6-6-5; pentacyclic: hopane/lupane skeletons) [22][141] |
Structural diversity of sesquiterpenoids arises from STS-mediated cyclization of FPP. For example, endophytic STSs from clusters 3, 4, 5, and unclustered groups produce distinct sesquiterpenes: cluster 3 STSs yield caryophyllene and its isomers (up to 80% of total products), cluster 4 STSs produce β-chamigrene, cluster 5 STSs generate τ-gurjunene, and unclustered EC12-SS and EC12-ILS produce α-selinene and (-)-isoledene, respectively [143]. In Populus trichocarpa, PtTPS1 accepts FPP to produce over 40 cyclic sesquiterpenes dominated by germacrene D, while PtTPS2 forms (E,E)-α-farnesene (95% of total product) [144]. In Hericium erinaceus, seven STS genes form three clades encoding linoleate 10R-lipoxygenase, alpha-muurolene synthase, and trichodiene synthase [145]. FPP itself is synthesized via two sequential condensation reactions of IPP with DMAPP into GPP, followed by condensation with another IPP molecule [142].
Triterpenoid structural diversity stems from OSC-mediated cyclization of 2,3-oxidosqualene—the first committed and diversifying step in their biosynthesis [20][22]. Plant OSCs are divided into P and D groups: P group OSCs (e.g., cycloartenol synthase, lanosterol synthase) generate tetracyclic skeletons via a chair-boat-chair (CBC) configuration, while D group OSCs produce pentacyclic skeletons (e.g., lupeol, β-amyrin) via a chair-chair-chair (CCC) configuration [22]. Neem tissues exhibit tissue-specific triterpenoid profiles: seed kernels are rich in C-seco triterpenoids (e.g., azadirachtin, salannin), while pericarps, flowers, and leaves contain ring-intact structures (e.g., azadirone, gedunin) [102]. Triterpenoid skeletons are further modified by tailoring enzymes like cytochrome P450s, UDP-glycosyltransferases, and acyltransferases, with glycosylation enhancing stability, solubility, and compartmentalization [22]. The triterpene intermediate squalene is synthesized by coupling two FPP molecules head-to-head via squalene synthase, followed by oxidation into 2,3-squalene epoxide by squalene epoxidase (NADPH-dependent) [142]. OSCs can be single-product (e.g., lupeol cyclases) or multifunctional (using dammarenyl cation intermediates) [141]. In saponin biosynthesis, OSC-mediated cyclization of linear precursors to polycyclic structures (e.g., β-amyrin) marks the branch point between primary and specialized triterpene metabolism in higher plants [146].
Biosynthetic pathways for sesquiterpenoids and triterpenoids diverge at the precursor level but share the cytosolic mevalonate (MVA) pathway as a source of IPP and DMAPP [147][148][149][150]. Prenyltransferases direct precursor flow: farnesyl diphosphate synthase (FPPS) forms FPP (C15) for sesquiterpenoids, while squalene synthase (SQS) condenses two FPP molecules to form squalene (a triterpenoid precursor) [20][22][102]. The MVA pathway plays a critical role in terpenoid precursor synthesis [151]. In Gynostemma pentaphyllum, both the cytosolic MVA pathway (end product IPP) and plastidial DXP (MEP) pathway (end products IPP and DMAPP) are present, with triterpene aglycones like protopanaxadiol synthesized from 2,3-oxidosqualene [150]. In cannabis, the MVA pathway supplies precursors for both sesquiterpenoids and triterpenoids [147]. In H. erinaceus, low squalene epoxidase expression explains its low triterpenoid content relative to other medicinal mushrooms [145]. Saponin biosynthesis starts with acetyl-CoA condensation in the MVA pathway, ultimately leading to 2,3-oxidosqualene [146].
Enzymatic regulation involves prenyltransferases and synthases. In Planococcus citri, transIDS5 (an FPPS-like enzyme) has high specific activity for C10/C15 prenyl diphosphate production and low irregular activity forming lavandulyl and maconelliyl diphosphate [152]. In H. erinaceus, three terpenoid gene clusters include STS, SQS, and CYP450 genes [145]. In Gossypium hirsutum, marker genes like (+)-δ-cadinene synthase (GhTPS-C2, GhTPS-XC14) are involved in sesquiterpenoid and triterpenoid biosynthesis [153]. In Neem, AiSQS (the first committed triterpenoid enzyme) is highly expressed in fruits, correlating with triterpenoid accumulation [102]. In the MVA pathway, genes encoding thiolase family proteins, HMG-CoA synthase proteins, GHMP kinase family proteins, isopentenyl diphosphate:dimethylallyl diphosphate isomerase, acetoacetyl-CoA thiolase 2, and mevalonate kinase show differential expression across conditions, indicating regulatory roles in precursor supply [151]. In saponin biosynthesis, cytochrome P450 (CYP P450) enzymes introduce hydroxyl groups via oxidation, followed by tailoring by transferases like UDP-dependent glycosyltransferases (UGTs) [146]. A lacking hemolytic activity (lha) mutant of Medicago truncatula has a defect in CYP716A12 (the first enzyme in the hemolytic sapogenin pathway), preventing hemolytic sapogenin synthesis while nonhemolytic soyasapogenol synthesis remains unaffected [146]. Through representative case studies of sesqui- and triterpenoid production, synthetic biology approaches have been practically implemented, highlighting exceptional achievements in production metrics [154].
Biosynthetic Pathways and Regulatory Mechanisms of Sesquiterpenoid and Triterpenoid Production
Structural Classification and Biosynthetic Precursor Divergence of Sesquiterpenoids and Triterpenoids
Terpenoid Biosynthesis Pathways and Substrate Specificity
Terpenoids (isoprenoids) derive from two core pathways: the cytosolic mevalonate (MVA) pathway and plastidial deoxyxylulose phosphate/methyl-erythritol phosphate (DOXP/MEP) pathway, both producing isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP) [147]. While the MVA pathway typically supplies sesquiterpenoid (C15) and triterpenoid (C30) precursors, and the MEP pathway supplies monoterpenoid (C10) and diterpenoid (C20) precursors [147][155], pathway crosstalk and species-specific variations are common. IPP is isomerized to DMAPP by IPP isomerase; these compounds form geranyl diphosphate (GPP, C10), farnesyl diphosphate (FPP, C15), and geranylgeranyl diphosphate (GGPP, C20) via prenyl transferases [156][157]. Terpene synthases/cyclases then generate terpenoid carbon skeletons, with cytochrome P450s mediating subsequent modifications [156][157].
Terpenoid Pathway Contributions and Key Enzymes Across Species
| Organism | Pathway Dependence & Key Observations | Key Enzymes/Gene Families Identified | Citations |
|---|---|---|---|
| Snapdragon flowers | MEP pathway contributes to monoterpene/sesquiterpene biosynthesis (IPP/DMAPP export to cytosol); MVA pathway does not contribute to nerolidol (low HMGR expression) | HMGR (low expression) | [158][159] |
| Daucus carota hairy roots | MEP pathway dependence for monoterpene/sesquiterpene emission (clomazone eliminated/reduced levels) | DXS (MEP pathway target) | [160] |
| Vitis vinifera cv. Lemberger | Both MVA and DOXP/MEP pathways contribute to sesquiterpenes; comparable deuterium-labeled precursor incorporation across harvest years | — | [161] |
| Vitis vinifera cv. Gewürztraminer | DOXP-derived label preferentially incorporated into acyclic sesquiterpenes (e.g., (E,E)-β-farnesene) | — | [161] |
| Elsholtzia species | MVA pathway/sesquiterpene biosynthesis genes more highly expressed in inflorescences than leaves | AACT1, HMGS, HMGR3, FPPS1 | [162] |
| Hedera helix L. | 339 unigenes in terpenoid backbone biosynthesis; 71 in sesquiterpenoid/triterpenoid biosynthesis | 6 MVA (AACT, HMGS, HMGR, MVK, PMVK, MVD); 8 MEP (DXS, DXR, ispD, ispE, ispF, ispG, ispH, IDI); 6 carbocyclic (GPS, GGPS, FPS, SS, SE, β-AS) | [163] |
| Wintersweet | MVA pathway generates sesquiterpenes; MEP pathway produces monoterpenes/diterpenes | 46 pathway genes; 52 CpTPSs (18 TPS-a, 24 TPS-b; CpTPS42 = nerolidol synthase) | [164] |
| Phallus cremeo-ochraceus | Terpene skeletons synthesized via cytoplasmic MVA pathway | HMGR, IPT, FPPS, GGPPS | [165] |
| Antrodia camphorata | 5 key triterpenoid biosynthesis enzymes with enhanced transcript levels in mutant E3-64; 13 terpenoid backbone genes identified | MVD, CYP, SQS, SE, OSC/LS; HMGS, HMGR, MPK, MVD, IDI, GPP, FPP | [166] |
| Prunellae Spica | MVA pathway more active than MEP pathway; triterpenoids accumulate during fruit maturation | — | [167] |
| Passion fruit | Both MVA and MEP/DOXP pathways involved in terpenoid biosynthesis | HMGS, HMGR, DXS, DXR, MDS, HDS, SM (key triterpenoid gene) | [168] |
| Toona sinensis | 67 DEGs enriched in terpenoid synthesis; 34 DEGs in sesquiterpenoid/triterpenoid biosynthesis | — | [169] |
| X. dendrorhous (fungi) | Terpenoids synthesized via MVA pathway | Acetyl-CoA condensation, mevalonate formation, prenyl pyrophosphate chain extension enzymes | [170] |
| G. pentaphyllum | All ginsenoside pathway genes (including SQS, SQE) present in EST library; terpenoid genes identified | — | [150] |
| Lagerstroemia indica | Key MVA/MEP pathway enzymes identified; HMGR most highly expressed | HMGR | [64] |
| Neem | AiSQS (first committed triterpene enzyme) 5x more expressed in fruit than leaves, 10x more than flowers; 12 short-chain prenyltransferases identified | AiSQS; 2 GDS, 9 GGDS, 1 FDS | [102] |
| Hericium erinaceus | Low squalene epoxidase expression may limit triterpenoid production | Squalene epoxidase | [145] |
Terpenoid Classification and Triterpenoid Biosynthesis
Terpenoids are classified by carbon count: monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), and triterpenes (C30) [171][150]. Sesquiterpenes (3 isoprene units) form mono-/bi-/tricyclic structures (over 7000 characterized), with sesquiterpene lactones common in natural remedies [141]. Triterpenes (6 isoprene units, 30 carbons) include pentacyclic hopane/lupane skeletons [141]; virgin olive oil’s main triterpenes are oleanolic acid, maslinic acid, and erythrodiol (8.9–112 mg/kg) [172]. In prenol lipids, triterpenes (28.4%), sesquiterpenes (18.2%), and diterpenes (18.2%) are dominant [173].
Triterpenoid biosynthesis starts with FPP: squalene synthase (SQS) condenses two FPP molecules to squalene, squalene epoxidase (SQE) converts squalene to 2,3-oxidosqualene, and oxidosqualene cyclases (OSCs) cyclize this to skeletons like β-amyrin or cycloartenol [171]. OSCs are divided into the P group (tetracyclic skeletons via chair-boat-chair configuration) and D group (pentacyclic skeletons via chair-chair-chair configuration) [22]. Plant OSCs include single-product (e.g., lupeol cyclases) and multifunctional enzymes [141]. Phylogenetic analysis of 13 Brassicaceae genomes identified 163 OSC genes in three clades; Clade II OSCs associate with CYP/ACT genes for triterpene modification [174]. Triterpene skeletons are further modified by CYPs (e.g., C28 oxidation by NaCYP716A419, C6β oxidation by NaCYP716E107) [175] and glycosyltransferases (forming glycosylated triterpenes like asiaticoside) [171]. Overexpression of Erg8, Erg9, and HFA1 increased β-amyrin production by ~500% [176].
Terpene Synthases (TPSs) and Functional Diversity
TPSs drive terpenoid structural diversity, with phylogenetic classification into seven subfamilies (TPS-a to TPS-h); TPS-a and TPS-b are most abundant in plants [177][178]. These subfamilies contain conserved motifs: N-terminal R(R)X8W (isomerization/cyclization) and C-terminal DDxxD/NSE/DTE (metal ion chelation for substrate cleavage) [177][179][3].
TPS Subfamily Distribution and Functional Examples
| Organism | TPS Subfamily Distribution & Key Functions | Citations |
|---|---|---|
| Dendrobium officinale | 88.2% of DoTPS proteins in TPS-a/TPS-b; most have conserved DDxxD motifs | [177] |
| Cucumber | TPS-a (CsaTPS11/12/14/15) uses FPP to produce α-himachalene, trans-a-bergamotene, cyclosativene; TPS-g/b/a localized to chromosomes 1/2/3 | [180] |
| Ocimum sanctum (Holy basil) | Sesquiterpene synthases in TPS-a2, TPS-b, TPS-g; OsaTPS02/12 = β-caryophyllene/α-humulene; OsaTPS07 = (-)-eremophilene | [179] |
| Hypoxylon sp. (endophyte) | Cluster 3 = caryophyllene isomers; Cluster 4 = β-chamigrene; EC12-ILS = first isoledene synthase | [143] |
| Populus trichocarpa | PtTPS1 (TPS-a) uses FPP for germacrene D-dominated mixture; PtTPS2 (TPS-a) produces (E,E)-α-farnesene | [144] |
| Vitis vinifera | VvTPS-a = sesquiterpene synthases; VvPNCuCAD = cubebol/δ-cadinene/α-copaene; VvPNaHum = α-humulene/hyemalol; VvPNLinNer1 = bifunctional (GPP→linalool, FPP→nerolidol) | [181] |
| AcTPS3 (fungi) | Clade IV Class I TPS; uses FPP to produce (+)-cubenene; has conserved DDXXD/NSE motifs | [3] |
| Rose | RcTPS23 (TPS-g) = bifunctional (GPP→linalool, FPP→nerolidol) | [182][178] |
| Wintersweet | 52 CpTPSs (18 TPS-a = sesquiterpene synthases; 24 TPS-b = monoterpene synthases; CpTPS42 = nerolidol) | [164] |
| — (transcriptome study) | 65 TPS unigenes: 20 monoterpene, 3 sesquiterpene (α-humulene/β-caryophyllene, (−)-germacrene D), 29 diterpene, 12 triterpene (β-amyrin, squalene monooxygenase) | [183] |
| — (EST analysis) | Up-regulated genes: monoterpene synthase (3 ESTs), terpene cyclase (9), (R)-limonene synthase (2), β-amyrin synthase (2), multifunctional triterpene synthase (1), lupeol synthase (1), myrcene synthase (11), pinene synthase (1) | [36] |
| Talaromyces verruculosus/Macrophomina phaseolina (fungi) | Chimeric class I triterpene synthases (TvTS/MpMS) with PTd/TCd domains; TvTS = talaropentaene (C1–III–IV cyclization); MpMS = macrophene (uncommon C1–VI cyclization) | [184] |
Additional Regulatory and Metabolic Observations
TPS gene clusters are often tandemly localized (e.g., cucumber TPS subfamilies on distinct chromosomes) [180]. In cotton, GhTPS-C2 and GhTPS-XC14 link sesquiterpenoid/triterpenoid biosynthesis to disease resistance [153]. Salinity negatively impacts terpenoid metabolism (e.g., plankton Pfam domains correlate negatively with salinity) [185]. KEGG analyses frequently enrich unigenes in sesquiterpenoid/triterpenoid biosynthesis, including hub genes (e.g., GH_D09G0090, GH_A13G1576) involved in gossypol biosynthesis and pigment gland development [186]. Fungal squalene–hopene cyclases (AacSHC, ZmoSHC1) show substrate scope differences: ZmoSHC1 converts homofarnesol to ambroxan more efficiently than AacSHC, and both produce sclareolide from homofarnesoic acid [187]. Plant in vitro cultures (e.g., hairy roots) use 2,3-oxidosqualene cyclization as a branch point between sterol and triterpenoid metabolism [188].
Terpenoid Metabolic Gene Clusters and Core Enzyme Characterization Across Taxa
Terpenoid biosynthesis, spanning sesquiterpenoid and triterpenoid pathways, is a conserved yet diversely regulated process across plants, fungi, and other organisms, with key roles in traits like fragrance, stress resistance, and secondary metabolite production [708, 1025, 1029, 1168, 724, 753, 773, 782, 794, 805, 825, 835, 844, 850, 976, 1018, 1023, 1129, 1072, 1074, 1142, 1111]. Two core pathways underpin terpene skeleton production: the mevalonate (MVA) pathway (dominant for sesquiterpenes, triterpenes, and steroids) and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway (for monoterpenes and diterpenes) [708, 1025, 1029, 794, 805, 850, 976]. Genomic and functional analyses across species reveal variability in pathway gene counts, enzyme specialization, and regulatory mechanisms, often linked to metabolic trait diversity.
Key Terpenoid Biosynthesis Genes, Enzymes, and Pathway Features Across Organisms
| Organism | Pathway/Enzyme Category | Key Findings | Citations |
|---|---|---|---|
| Wintersweet | MVA/MEP pathways | 46 genes identified; expanded families enriched in sesquiterpenoid/triterpenoid biosynthesis | [164] |
| Wintersweet | Terpene synthases (TPS) | 52 complete CpTPSs; 18 TPS-a (sesquiterpene), 24 TPS-b (monoterpene); CpTPS42 produces nerolidol | [164] |
| Mango | MVA pathway gene families | HMGR (4 members), trehalose-6-phosphate synthase (TPS, 4 members) identified | [189] |
| G. barbadense (cotton) | TPS genes | 115 TPSs (44 monoterpene, 59 sesquiterpene, 8 diterpene, 4 triterpene/squalene synthases) | [190] |
| G. barbadense (cotton) | Sesquiterpene synthase | 19 (+)-δ-cadinene synthase (CDN) genes (first step of gossypol biosynthesis) | [190] |
| Grafted GSCL vs. SCL | Differential terpenoids/DEGs | 109 differential terpenoids (37 sesquiterpenoids, 59 triterpenoids; most elevated); 19 triterpenoid biosynthesis unigenes (10 upregulated: HMGCS, MVK/mvaK1, MVD/mvaD, SQLE/ERG1, LUP1); MVA pathway major for triterpenoids | [191] |
| Ferns | Triterpenes/Squalene cyclases (SCs) | Most produce triterpene hydrocarbons; SCs phylogenetically distant from bryophyte SCs (independent acquisition) | [192] |
| Fungi (T. verruculosus, M. phaseolina) | Bifunctional triterpene synthases | TvTS (PTd/TCd domains: HexPP synthesis → talaropentaene); MpMS (uncommon C1–VI cyclization) | [184] |
| Phallus cremeo-ochraceus | MVA pathway/genome annotation | Key enzymes: HMGCR, IPT, FPPS, GGPPS; 31 terpene skeleton, 5 sesquiterpene/triterpene, 29 steroid biosynthesis genes | [165] |
| Ganoderma lucidum | Triterpenoid biosynthesis | MVA pathway; lanosterol intermediate; LSS (key); 78 CYPs coexpressed with LSS (r>0.9); 24 gene clusters (2 with LSS-coexpressed CYPs) | [193] |
| Neem | Triterpenoids/key enzyme | Kernel: C-seco triterpenoids (azadirachtin); pericarps: ring-intact triterpenoids (azadirone); AiSQS (committed enzyme) highly expressed in fruit | [102] |
| CSR3 genome | MVA pathway/triterpene cyclization | 18 MVA enzymes; LSS catalyzes triterpene cyclization | [194] |
| ApOSCs (plant species) | Oxidosqualene cyclases | Monofunctional β-amyrin synthase (ApOSC4); multifunctional (ApOSC6/7/8: β-amyrin, α-amyrin, other triterpenoids) | [195] |
| Astragalus membranaceus (AMM) | Triterpenoid enzymes/clusters | 18 biosynthetic enzymes (MVA genes highly expressed in roots); 24 secondary metabolism clusters (3 triterpenoid: I=3 bAS, II=1 LUS, III=1 LAS, 2 CAS, 2 LUS); Cluster III OSCs (cycloatenol, lupeol) functional | [196] |
| A. membranaceus hairy roots | Triterpenoid genes | 10 genes (AmAACT, AmHMGS, AmHMGR1-3, AmMK, AmPMK, AmMVD, AmFPS, AmSE, AmCAS) highly expressed in stems/leaves; astragalosides accumulate in roots | [197] |
| Tobacco | TPS genes/BGCs | 160 TPSs (5 clades; 95 TPS-a/sesquiterpene); 7 terpene BGCs (some with TPS-CYP pairs) | [198] |
| Populus trichocarpa | HMGR enzyme | PtHMGR has conserved HMG-CoA/NADP(H)-binding domains; overexpression upregulates downstream MVA genes | [199] |
| Ziziphus jujuba var. spinosa | HMGR gene family | 3 conserved ZjHMGR isoforms (related to P. trichocarpa); cis-elements: MYB-related, TC-rich, light/hormone-responsive; upregulated under ABA, MeJA, light, saline stress; overexpression enhances Arabidopsis salt resistance | [200] |
| Brassicaceae (13 genomes) | Oxidosqualene cyclases (OSCs) | 163 predicted OSCs (3 clades: sterol, I, II); clade II OSCs associated with CYP/ACT (scaffold-modifying enzymes); OSCs produce tirucallol/euphol, modified by neighbouring CYPs/ACTs | [174] |
| Yeast (strain 1031.βA) | Ergosterol/β-amyrin production | Simultaneous overexpression of Erg8, Erg9, HFA1: 46 mg/g DW ergosterol; 500% β-amyrin increase vs. control | [176] |
| Toona sinensis | Terpenoid components/DEGs | Main components: monoterpenes/sesquiterpenes; 67 DEGs in terpenoid pathways (34 in sesquiterpenoid/triterpenoid biosynthesis) | [169] |
| G. leucocontextum | Ganoderic acid/ergosterol pathways | 26 terpenoid backbone, 3 sesquiterpenoid/triterpenoid genes; intact sesquiterpenoid/triterpenoid pathway (incomplete in G. lucidum); lacks ERG11-2 (substituted by ERG11-1) | [201] |
| Triterpene cyclases (AacSHC, ZmoSHC1) | Substrate specificity | ZmoSHC1 higher conversion of homofarnesol to ambroxan; both convert homofarnesoic acid to sclareolide; farnesylacetone → sclareoloxide; AacSHC converts nerolidol to (–)-caparrapioxide/8-epi-caparrapioxide; geranylacetone → cyclic enol ether; ZmoSHC1 favors shorter carbon-chain substrates | [187] |
Gene clusters are a recurring feature in terpenoid biosynthesis, with genomic organization in some organisms grouping GGPPS, mono/sesquiterpene synthases, triterpene synthases, and squalene monooxygenases [202]. Squalene synthase, a bifunctional membrane enzyme, catalyzes FPP condensation to presqualene diphosphate (PSPP) and PSPP rearrangement to squalene; its human homolog (PDB ID: 1ezf) shares active-center α-helix structure with other isoprenoid enzymes [176]. Across taxa, regulatory mechanisms include transcriptional control (e.g., ZjHMGR cis-elements responding to hormones/light [200]) and enzyme specialization (e.g., bifunctional fungal TPSs [184] or multifunctional plant OSCs [195]), highlighting the adaptability of terpenoid pathways to diverse biological needs.
Environmental and Hormonal Regulation of Sesquiterpenoid and Triterpenoid Accumulation
Sesquiterpenoid and triterpenoid biosynthesis share a conserved precursor, farnesyl diphosphate (FPP), which is converted to sesquiterpenoids via terpene synthases (TPS) and to triterpenoids through squalene (a product of FPP dimerization) [203]. In ginseng roots, FPP directly generates sesquiterpenoids (germacrene, solavetivone, valencene/7-epi-α-selinene), with TPS1/CYP71D55 highly expressed in FCG roots and germacrene D synthase (GERD) more abundant in MCG roots [203]. For triterpenoids, FPP-derived squalene is oxidized to 2,3-oxidosqualene by squalene epoxidase (SQLE), branching into steroid and ginsenoside pathways; β-amyrin synthase (β-AS), dammarenediol II synthase (DS), and PDS are upregulated in FCG roots, favoring triterpenoid/PPD-type ginsenoside production [203]. GC-MS profiling confirmed dominant sesquiterpenoid accumulation in MCG roots (e.g., germacrene D) and triterpenoid accumulation in FCG roots (e.g., alpha-amyrin, gamma-sitosterol) [203].
In other species, terpene biosynthesis follows analogous pathways: in R. bailiense, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) are synthesized via the cytosolic mevalonate (MVA) and plastidial methylerythritol phosphate (MEP) pathways, respectively, then condensed to FPP (C-15) for sesquiterpenoid production [204]. R. bailiense has a higher copy number of sesquiterpene-related TPSs (94 vs. 31 in R. molle) and more TPSs with TPM >1 (8 vs. 7), suggesting greater sesquiterpene synthesis activity [204]. In vitro-cultured R. bailiense calli show more abundant sesquiterpene TPS expression than wild materials [204]. In grape development, 10 TPS-b transcripts exhibit differential expression (young berries, veraison, ripe berries) [205].
For triterpenoid biosynthesis, S. lonicericola has 11 MVA pathway enzymes (encoded by 30 genes) with lanosterol as a key intermediate [206]. Codonopsis pilosula roots have 15 distinct triterpenoids/sesquiterpenoids (10 differentially accumulated by origin), with 46 candidate genes (20 skeleton synthesis, 26 triterpenoid/sesquiterpenoid generation/modulation) identified via Mfuzz and WGCNA [207]. In Athelia termitophila (TMB), AtAACT and AtMVD catalyze key MVA pathway steps for triterpenoid precursors [208]. Prunellae Spica has a more active MVA pathway (7 proteins/75 genes) than MEP (10 proteins/23 genes), with triterpenoids accumulating significantly during fruit maturation (p < 0.05) [167]. Toona sinensis has 34 DEGs in the sesquiterpenoid/triterpenoid pathway [169]. T. gaoligongensis shows cultivation-dependent differences in antcin/antrodin C biosynthetic genes, with TgHMGR highly expressed in NZJB (correlating with elevated terpenoid levels) [209]. Ziziphus jujuba var. spinosa has three conserved ZjHMGR isoforms with tissue-specific and salt-responsive expression [200]. C. reinhardtii forms squalene (triterpenoid precursor) from two FPP molecules [210]. G. biloba roots have the highest TTL content, with 40 DECYP450s (r>0.89, P<0.01) and a turquoise WGCNA module (r=0.99, P<0.01) linked to TTLs [211].
Regulatory mechanisms of sesquiterpenoid and triterpenoid biosynthesis involve transcription factors (TFs) and microRNAs (miRNAs). In Atractylodes lancea, AlWRKY20/AlWRKY37 bind to AlTPS70/AlTPS71 promoters, positively regulating cis-beta-farnesene/alpha-curcumene production and responding to methyl jasmonate (MeJA) [212]. In tomatoes, SlMYC1 (JA signaling) modulates MEP/MVA pathway genes for sesquiterpenoid precursors [213]. miRNAs target biosynthetic genes: miR156 upregulates TPS21 via SPL9 [214]; miR1134/miR5021/miR7539 target upstream enzymes in Xanthium strumarium [214]; miR166i-3p regulates biosynthesis in Chlorophytum borivilianum [215]. Spruce PtMYB14 increases sesquiterpene diversity/amounts, with MVA pathway/terpene synthase transcripts accumulating alongside PgMYB14/PtMYB14 in pine/spruce [216]. R. bailiense has more active monoterpene/sesquiterpene TPSs than R. molle [204]. Key sesquiterpene pathway genes (DXS1, HMGR, FPS, AsSS1, AsTPS) show differential expression under Agar-Bit/BCD stimulation, with up to 1100-fold increases in BCD [217]. C. pilosula CpbHLH2/3 and CpAP2/ERF2 directly regulate triterpenoid/sesquiterpenoid biosynthetic genes [207]. W. cocos erg11/FDPS correlate positively with (+)-pulegone [218]. Apple MdOSC1 and CYP716A1-like genes are more abundant in non-russeted skin, with suberin-related triterpene synthesis involving lupeol synthase/SQE1/CYP450 and BAHD acyltransferases [219]. EST analysis identifies upregulated triterpene synthases (β-amyrin, multifunctional, lupeol) [36]. C. reinhardtii MYB overexpression upregulates SQS and increases squalene content [220]. T. gaoligongensis TFs (TgHSF4, TgMYB6, etc.) may regulate biosynthetic genes [209]. G. biloba GbCYP450s have MeJA-responsive elements, with MeJA altering expression [211]. Z. jujuba var. spinosa ZjHMGR has MYB-related/hormone-responsive elements [200]. Friction-damaged kiwifruit has nine TFs influencing JA/triterpene synthesis [221].
Environmental and hormonal factors modulate sesquiterpenoid and triterpenoid accumulation. MeJA induces sesquiterpenoid emission (up to 1000-fold) in Carpinus betulus, Quercus robur, and Tilia cordata [222], and upregulates MEP/MVA pathway genes/TPSs in tomatoes [213]. Wintersweet CpFPPS expression correlates with sesquiterpenoid emission (highest in petals/leaves) [223]. Heavy metal stress (Pb) enriches the biosynthesis pathway in tall fescue [224]. Wounding induces sesquiterpene production in Angelica sinensis via H2O2 and AsTPS upregulation [225]. Fungal infection (E. polonica) increases sesquiterpenes (3–7-fold) and IDS4 expression in trees [226]. Weevil feeding increases conifer sesquiterpene emissions 8-fold [227]. Drought increases sesquiterpenes via ABA-independent pathways [228]. Light intensity affects Atractylodes lancea: 80% shading maximizes hinesol/β-eudesmol levels (correlating with HMGR/DXR/FPPS expression) [229]. TOR signaling positively regulates tomato trichome development (sesquiterpene site) [213]. Elicitors have distinct effects: MeJA upregulates sesquiterpenoids (e.g., gossypol), while SA/MJSA target triterpenoid precursors [230]. Dark conditions enhance R. bailiense callus sesquiterpene derivatives (Germacrone, Oleuropein), while light promotes triterpenes (Ilexgenin A, Ganolucidic acid) [204]. Ozone stress enriches the biosynthesis pathway in ME39 [231]. Ganoderma lucidum triterpenoid production increases with amphotericin (1.52 g/L at 72 h) [232]. Mn²+ (10 mM) enhances triterpenoid content (2.03-fold) via MVA pathway activation [233]. C. paliurus ANE elicitation involves NO/H2O2/JA, with JA as the critical signal [234]. PBZ increases S. lonicericola triterpenoid diversity and MVA pathway expression [206]. Low-dose MeJA (1 mM) increases R. roxburghii triterpenoid content and pathway gene expression [235]. Oleic acid (2%) and MeJA (100 mol/L) boost triterpene yield [236]. High cobalt alters B. braunii botryococcene/squalene pathway transcription [237]. HLB-affected citrus shows negative correlations between monoterpenes and sesquiterpenes [238]. SA treatment (200 μmol/L) increases TMB triterpene content (26% higher) and MVA gene expression [765, 852]. Vibrio stress upregulates U. fasciata sesquiterpenoid/triterpenoid biosynthetic genes [239]. Temperature changes alter pathway gene transcription (heat affects terpenoid biosynthesis, cold affects backbone synthesis) [240]. PGRs affect HE samples: BA HE has more triterpenoids, GA3 HE has more sesquiterpenoids [241]. Linolenic acid upregulates MVA genes and increases triterpenoid production (2.6-fold) [242]. T. gaoligongensis NZJB/XZJB have 7-fold/3.9-fold higher triterpenoid content than DM [209]. G. biloba MeJA treatment increases leaf TTL content by 60.15% [211]. Z. jujuba var. spinosa ZjHMGR is upregulated by ABA/MeJA/light/saline stress [200]. C. reinhardtii MeJA treatment increases squalene (4-fold) and SQE expression, while decreasing sterols [210]. Friction-damaged kiwifruit shows increased JA and triterpene content [221].
Functional Engineering and Metabolic Pathway Modulation of Terpenoid Production
Terpenoids, the largest class of natural products, are traditionally derived from C-5 isoprene units, but recent work shows modified C-5 units can produce non-natural terpenoids via modification enzymes[243]. For example, combining geranyl pyrophosphate C6 methyltransferase BezA with promiscuous prenyltransferase NphB enabled synthesis of five methylgeranylated flavonoids from naringenin, apigenin, and genistein, highlighting BezA’s utility for novel terpenoid production[243].
Characterization and Engineering of Selina-4(15),7(11)-Diene Synthase (SdSWT) from Streptomyces pristinaespiralis
| Parameter | Wild-Type SdSWT | SdSWT G305E Mutation |
|---|---|---|
| Reaction Catalyzed | Formation of selina-4(15),7(11)-diene and germacrene B from (2E,6E)-FDP[244] | Synthesis of selin-7(11)-en-4-ol (20%) and selina-4(15),7(11)-diene (52.9%)[244] |
| Product Origin | Germacrene B: C10 deprotonation of carbocation A; selina-4(15),7(11)-diene: C15 deprotonation of carbocation B[244] | Selin-7(11)-en-4-ol: Water addition to C3 of carbocation B (C4 stereocenter confirmed as S by 2D NMR)[244] |
| Water Access Mechanism | No water approach to C3[244] | Water access enabled; pre-S water coordination by PPi and E305 explains stereospecificity[244] |
| pH Optimization Outcome | N/A | Selin-7(11)-en-4-ol formation increased to 47.8% at pH 6.0[244] |
| Bacterial Culture Production | N/A | 9.8 ± 1.2 mg/L[244] |
Upper-stream sesquiterpene pathway enzymes (DXS1, HMGR, FPS) show distinct expression patterns across stimulation groups[217]. In the Agar-Bit group, these genes were down-regulated post-stimulation, peaking at 1 month (AsDXS1) or 3 months (others) before returning to minima by 4 months[217]. For the BCD group, they peaked at 5 months (FPS at 100-fold above control) and sharply declined at 6 months[217]. Pathway-specific enzymes (AsSS1, TPS) also vary: AsSS1 decreased post-Agar-Bit stimulation but peaked at 3 months, while in BCD it reached 1000-fold control at 5 months[217]; AsTPS in BCD peaked at 6 months, with 5-month levels ~1100-fold control[217]. Ten sesquiterpene synthases (STPSs) with documented activity and complete sequences (e.g., selinene synthase, UniProt: O64404; vetispiradiene synthase, NCBI: QBB02271.1, UniProt: A0A411G8M5) were selected for functional characterization[245]. Multiple sesquiterpenes (e.g., aristolochene, valencene, patchoulol) were produced in engineered systems with yields of ~250–2500 μg L−1[245]. Oxy-functionalization via CYPs yielded specific derivatives, as detailed in the table below. A mevalonic acid (MVA) platform strain transformed with ERG20 (FPP synthase) and ZSS1 (α-humulene synthase from Zingiber zerumbet) produced ~60-fold more α-humulene than wild type in 24 h[246]; ERG20-ZSS1 fusion constructs yielded half as much, likely due to unfavorable conformational properties[246].
Oxy-Functionalization of Sesquiterpenes via Cytochrome P450s (CYPs)
| CYP (UniProt ID) | Substrate(s) | Product(s) | Efficiency |
|---|---|---|---|
| CYP02 (W6QP06) | Aristolochene | Aristolochone | 45±21%[245] |
| CYP04 (E1B2Z9) | Valencene | Nootkatone | 62±18%[245] |
| CYP09 (VR5EU4) | Santalene | Bergamotol, santalol | 55±13%[245] |
| CYP10 (A0A0N9H930) | α‐cadinene/β‐cadinene/γ‐cadinene/muurolene | Muurolol, α‐cadinol | 51±8%[245] |
| CYP12 (E3W9C4) | α‐guaiene/β‐guaiene/δ‐guaiene/α‐humulene/alloaromadendrene | α‐guaiol, β‐guaiol, globulol, rotundone, alloaromadendrene oxide | 66±19%[245] |
Triterpenoids, such as the over 150 isolated from Ganoderma lucidum, are synthesized via the MVA pathway[193]. The upstream cyclization step involves 11 enzymes encoded by 13 genes (two genes each for acetyl-CoA C-acetyltransferases and FPS, single copies for others)[193]. Lanosterol (synthesized by LSS) is a common intermediate for triterpenoids and ergosterol, with downstream modifications likely involving CYPs[193]. G. lucidum has 197 functional CYP genes, 78 of which are upregulated during mycelia-to-primordia transition and correlate with LSS expression (r > 0.9) and triterpenoid content[193]; 15 CYP512 and one CYP5144 gene coexpressed with LSS are likely involved in triterpenoid biosynthesis[193]. Saponins (modified triterpenoids from a β-amyrin backbone) have industrial and health applications[247]. β-amyrin biosynthesis is achieved in E. coli and S. cerevisiae, but oxidized/glycosylated derivatives are limited to yeast[247]. Directed evolution of UGTPg45 enabled 2.25 g/L ginsenoside Rh2 production (the highest in vivo titer reported)[247]. Yeast systems (e.g., S. cerevisiae, Yarrowia lipolytica) benefit from an endogenous ER system, critical for engineering S. cerevisiae to produce oxidized casbenes (diterpenoid derivatives) via six CYP optimizations (titers >1 g/L), building on artemisinic acid production techniques[247].
Triterpenoid Production Enhancements via Stimulation and Genetic Engineering
| System | Stimulation/Modification | Outcome |
|---|---|---|
| G. lucidum mycelia | Ultrasound treatment | 34.96% triterpenoid increase (P < 0.05); MVA pathway enrichment (P < 0.01)[248] |
| G. lucidum | 10 mM Mn²+ | 2.03-fold total triterpenoid increase (28.7 ± 0.3 mg/g) via HMGS regulation[233] |
| S. cerevisiae (Sc-HS1) | Heterologous HMGS expression | Enhanced squalene production[233] |
| G. lucidum | Linolenic acid addition | 6.9–14.4-fold upregulation of HMGS, HMGR, FPPS, SQS, SE; 2.6-fold triterpenoid increase (539.8 mg/L)[242] |
| MVA platform strain | ERG20 + ERG9 (squalene synthase) + terbinafine (Erg1p inhibitor) | ~35-fold squalene increase vs. wild type[246] |
| MVA platform strain | ERG20-ERG9 fusion | ~50% squalene yield vs. non-fused constructs[246] |
| A. termitophila (TMB) | 200 μmol/L salicylic acid (SA) | 26% triterpene increase (41.83 ± 0.5 mg/100 mL); AtAACT peak at 36 h, AtMVD peak at 48 h[208][249] |
| A. termitophila | 200 μmol/L SA | 7.09-fold AACT, 2.8-fold SS, 23-fold MVD, 2.2-fold FPS upregulation; MVD/AACT/PMK/SE expression correlated with triterpenoid content (r = 0.86–0.72, p < 0.001)[249] |
Triterpenoid biosynthesis in Nicotiana tabacum (e.g., ursolic acid) occurs in the ER via the MVA pathway[250]. Co-expressing AtFPS2, ScERG9, ScERG1, MdOSC1, and MdCYP90-like produced ~2.1 µg/g FW ursolic acid in three plants (absent in wild-type or lines lacking MdOSC1/MdCYP90-like)[250]. RT-qPCR of tobacco lines overexpressing PmCMK showed increased NtDXS, NtDXR, NtHMGR, NtPSY, NtPDS, NtZDS, Ntβ-LCY, and NtBCH2 expression, alongside decreased NtGGPPS, NtMK, and NtTPS expression, indicating PmCMK’s complex regulatory role in terpene pathways[251].
In Azadirachta indica (Neem), triterpenoid profiles vary by tissue: kernels have C-seco triterpenoids (azadirachtin, salannin), while pericarps have ring-intact structures (azadirone, gedunin)[102]. AiSQS (first committed triterpene enzyme) is 5-fold more expressed in fruit than leaves and 10-fold more than flowers, correlating with triterpenoid abundance[102].
Astragalus membranaceus var. mongholicus (AMM) synthesizes astragalosides via MVA and MEP pathways[196]. MVA genes are root-specific (vegetative stage), while MEP genes are leaf-specific[196]. Oxidosqualene cyclases (OSCs: CAS, bAS, LAS, LUS) drive triterpenoid diversity, with bAS highly expressed in roots[196]. PlantiSMASH identified three triterpenoid gene clusters; cluster III’s Am07G013660 (cycloartenol) and Am07G013690 (lupeol) were functionally validated in yeast[196].
Algal Terpenoid Engineering Outcomes
| Modification | Patchoulol Yield (Pogostemon cablin PcPS) | Additional Effects |
|---|---|---|
| Wild type | 5.4 ± 2.1 fg/cell[252] | N/A |
| CrBKT overexpression | 8-fold increase[252] | N/A |
| CrSQS suppression | 12-fold increase[252] | N/A |
| Combined CrBKT overexpression + CrSQS suppression | 25-fold increase (132.7 ± 41.1 fg/cell; 2215 µg/L)[252] | Transgenic strains produced santalene, zizaene; STPS isoform activity varied by YFP placement; oxy-functionalization of 9 sesquiterpenoids matched natural agarwood profiles[252] |
| DXS overexpression (C. reinhardtii) | N/A | Increased zeaxanthin/antheraxanthin; 50% reduced lutein[253] |
| MYB overexpression (C. reinhardtii) | N/A | High SQS expression; ~90.20 μg/g squalene increase (carbon flux rerouted to triterpenoids)[220] |
Plant in vitro cultures (e.g., hairy roots) produce triterpenoids and sterols from squalene, with 2,3-oxidosqualene cyclization as a branch point between general (sterols) and specialized (triterpenoids) metabolism[188]. Triterpenoid biosynthesis predominates when sterol needs are met, aligning with growth-defense trade-offs[188]. Overexpression of IDS1 in needles increased IDS1 transcript (300–700-fold), protein, and GDP enzyme activity (7–17-fold), shifting prenyl diphosphate production to GGDP but not altering monoterpene, diterpene, or trace sesquiterpene levels[254]; bark tissue showed minimal effects[254].
In fungal systems, NZJB and XZJB cultivation methods enhanced triterpenoid production in T. gaoligongensis mycelium (sevenfold and 3.9-fold higher than DM, respectively)[209]. Antcins and antrodin C increased: antcin C (9.72-fold in XZJB), antcin I (12.83-fold in NZJB), and antrodin C (3.2-fold higher than GLG in NZJB)[209]. Transcriptome analysis revealed higher TgHMGR expression in NZJB (correlating with terpenoid levels), suggesting it is a key rate-limiting enzyme[209]. Co-expression and promoter binding site predictions indicated TgHMGR/TgFPPS2 may be regulated by TgHSF4/TgMYB6, while TgErg2/TgErg3/TgErg5/TgErg6_1 may be regulated by TgZnF1/TgMYB9/TgHOX1/TgHMG8[209].
Analytical Methods for Detection, Quantification, and Structural Elucidation of Terpenoids
Structural Classification and Skeletal Diversity of Sesquiterpenoids from Marine and Terrestrial Sources
Sesquiterpenoids exhibit extensive skeletal diversity across marine and terrestrial sources. Marine macroalgae of the Laurencia genus are particularly notable for biosynthesizing structurally diverse sesquiterpenes, with new structures reported since 2015 spanning multiple skeleton types [255]. Terrestrial sources also yield diverse sesquiterpenoids, including novel compounds from species like A. sieversiana and unspecified taxa, alongside known and newly identified compounds across various skeleton classes [313, 345, 455, 464, 607, 779, 790, 872]. Purification and isolation of sesquiterpenoids employ techniques such as MPLC, silica gel column chromatography, cycling HPLC, supercritical fluid extraction (SFE), high-speed counter-current chromatography (HSCCC), and activity-oriented isolation combining chromatographic methods with UFLC-MSn and HR-MS [134].
Sesquiterpenoid Structures by Source and Skeleton Type
| Source Category | Skeleton Type | Example Compounds | Citations |
|---|---|---|---|
| Marine (Laurencia) | Chamigrane | 7-aldehydelaurencenone B, lauremantanones A and B | [255] |
| Marine (Laurencia) | Bisabolane | Laurecomposins A and B | [255] |
| Marine (Laurencia) | Cuparane | 4α-hydroxybromocuparene, algoane | [255] |
| Marine (Laurencia) | Laurane | Nanji A, laurokamurols A–C | [255] |
| Marine (Laurencia) | Aristolane | Debilone | [255] |
| Marine (Laurencia) | Brasilane | 4-hydroxy-5-brasilene | [255] |
| Marine (Laurencia) | Eudesmane | Eudesma-4(15),7-diene-5,11-diol | [255] |
| Marine (Laurencia) | Snyderane | 8-keto-10-dehydrobromo-γ-snyderol | [255] |
| Marine (Laurencia) | Other | 3α-bromojohnstone, (+)-cyclocolorenone | [255] |
| Terrestrial | Tsarvanin | Tsarvanins A–C (with costuslactone B, artabsinolide A) | [114] |
| Terrestrial | Seco-pyrocurzerenone | 4,5-seco-pyrocurzerenone (with 16 sesquiterpenoids) | [256] |
| Terrestrial | Eudesmane | Eudesm-6-en-4β-ol, guai-6-en-10β-ol, eudesma-5,7-diene, eudesma-4,11-diene, α-selinene, eudesma-5,7-dien-2α-ol, 5α,6α,7α,8α-diepoxy-eudesmane, 5α,6α-epoxy-eudesm-7-ene, 5α,6α-epoxy-eudesm-7-en-9-ol | [12] |
| Terrestrial | Cadinane | Cinnamoid A, cinnamoid B, cinnamoid C, cinnamoid D, cinnamoid E, (−)-15-hydroxy-T-muurolol, 15-hydroxy-α-cadinol, (4α,10β)-4,10-dihydroxy cadin-1(6)-en-5-one, mustakone | [7] |
| Terrestrial | Eremophilane | 4S,5R,7S-8-oxoeremophila-9,11(13)-dien-12-al, 4S,5R,7R-8-oxoeremophila-9,11(13)-dien-12-al, 4S,5R,7S-12-(3′-Methylbutyryloxy)eremophila-9,11(13)-dien-8-one, 4S,5R-trinoreremophil-9-en-8-one, 7S- and 7R-eremophila-9,11-dien-8-one, eudesma-4,11-dien-1β-ol, 1β-hydroxyeudesma-4,11-dien-3-one | [257] |
| Terrestrial | Germacrane | Hydroxymikaperiplocolide A, hydroxymikaperiplocolide B, 3-dehydroxymikaperiplocolide | [258] |
| Terrestrial | Furanoeremophilane | (1S,4S,5R,10R)-1-hydroxy-6-isobutyryloxy-10H-9-oxofuranoeremophilane, 6-O-2-methylbutyryloxy derivative | [259] |
| Terrestrial | Guaiane | Coptosapterpene A (5(6),7(8),1(10)-guaiatrien-9-one) and its 4-hydroxy, 2-hydroxy derivatives | [113] |
| Terrestrial | Miscellaneous | Germacrene D, (E,E)-α-farnesene, (E)-β-farnesene, linalool, nerolidol, (E)-β-caryophyllene, α-humulene, sabinene, bicyclogermacrene, α-pinene, β-elemene, sesquithuriferol, spathulenol, (E)-nerolidol, τ-cadinol | [459, 722] |
Analytical methods for sesquiterpenoid detection and structural elucidation include gas chromatography (GC) coupled with flame ionization detection (FID) or mass spectrometry (MS), widely used for identifying terpenoids in plant parts and complex matrices [25, 126, 589, 733]. For structural characterization, primary techniques include high-resolution NMR (1H, 13C, COSY, HSQC, HMBC, NOESY), high-resolution electrospray ionization mass spectrometry (HRESIMS), and X-ray crystallographic analysis [27, 313, 345, 431]. HRESIMS determines molecular formulas for specific sesquiterpenoids [448, 464, 607, 779], while IR spectroscopy identifies functional groups like alkyl, carbonyl, hydroxyl, and olefinic moieties [448, 464, 607, 779]. 1D and 2D NMR techniques elucidate planar structures and stereochemistry [448, 455, 464, 607, 729, 779], with CD spectroscopy aiding absolute configuration determination [607, 779]. Advanced workflows include the NMR-coupled crystalline-sponge method for structures like laurinterol [255], molecular networking for Laurencia algae sesquiterpenes [255], and HPLC for chemical profiling of species such as L. tristicha and L. okamurai [255]. Additional methods include TLC, MALDI-TOF MS, FAB-MS, HR-DART-MS, and X-ray crystallography for C. rotundus sesquiterpenoids [134], as well as HRFABMS, UV spectroscopy, ROESY, and Mosher ester methodology for furanoeremophilane and guaiane-type compounds [790, 872]. Qualitative phytochemical screening for sesquiterpenoids uses TLC with vanillin–sulfuric acid or vanillin–phosphoric acid reagents [260].
Sesquiterpenoids are abundant in various natural matrices. In essential oils (EOs), they often dominate: an EO with 95 volatile compounds contained 18 sesquiterpenes and 11 derivatives (61.1% of total peak area) [261]; pigeon pea leaf EOs via subcritical fluid extraction (SFME) and hydrodistillation (HD) had sesquiterpenes as the most abundant components (72.89% and 65.26%, respectively) [55]; and L. camara leaf EO featured major sesquiterpenoids like (E)-β-caryophyllene (40.8%) and α-humulene (21.2%) [262]. Other sources include fruit intracuticular wax (farnesol) [263], G. guidonia leaf volatile oil (eudesm-6-en-4β-ol, guai-6-en-10β-ol) [12], E. maidenii outer bark [30], Trichoderma viride mycelia volatiles (34.07% sesquiterpenes) [264], M. americana L. bark extract (nerolidol, α-elemene, δ-cadinene) [265], E. dendroides latex (β-cedrene) [33], and S. terebinthifolia dichloromethane fraction (spatulenol, β-caryophyllene) [121]. LC–LTQ–MS–MS and molecular networking identified novel sesquiterpenoids (e.g., copaenol) in Lantana species [122], and sesquiterpenoid release increased during flower development stages [266].
Biotransformation studies highlight microbial modification of sesquiterpenoid structures. Aspergillus niger produced metabolites from (-)-ambrox, dehydrocostuslactone, α-, β-, γ-cyclocostunolides, α-santonin, and atractylon [267]. Mucor plumbeus hydroxylated polycyclic sesquiterpenoids (e.g., cedrane, clovane, patchouli alcohol series) at chemically inaccessible hydrophobic regions, with hydroxylation sites determined via 13C NMR, stereochemistry via 1H:1H coupling constants and X-ray crystallography, and hydroxyl group distances ranging from 4.2–6.6 Å [268].
Triterpenoids also exhibit structural diversity, with examples spanning multiple skeleton types. Purification and analysis methods include GC–MS, HRESIMS, IR spectroscopy, 1D/2D NMR, acid hydrolysis for glycosidic triterpenoids, qualitative screening via Bilbao’s method or TLC, colorimetric quantification, and metabolomic identification via UPLC-MS/MS and GC-MS [448, 589, 729, 803, 813, 828, 843, 1119].
Triterpenoid Structures by Skeleton Type
| Skeleton Type | Example Compounds | Citations |
|---|---|---|
| Dammarane | Compound 1 (C32H52O4), compound 2 (C31H50O4), compound 3 (C33H54O3), (23E)-dammara-20,23-diene-3β,25-diol, dammar-20,25-dien-3β,24-diol, dammaradienol, 24-methylenedammarenol, 3β-hydroxyeutio-17β-dammaranic acid, (3β,24S)-eupha-7,25-diene-3,24-diol | [8] |
| Norursane | Compound 4 (C29H42O5) | [8] |
| Ursane | Compound 5 (C30H44O5), 3-oxo-2,19-dihydroxy-24-nor-urs-1,4,12-trien-28-oic acid, ursolic acid, 3β,28-dihydroxyurs-12-ene, trans-3-O-p-hydroxycinnamoyl ursolic acid, urs-12-ene-3β,28-diol-3-acetate, neoilexonol, ilelatifol A, 11-oxoursolic acid, 2α,3α,24-trihydroxyurs-12-en-28-oic acid, 2α,3β,19α,23-tetrahydroxyurs-12-en-28-oic acid, 2α,3α,19α,24-tetrahydroxyurs-12-en-28-oic acid, 3β,19α,23-trihydroxyurs-12-en-28-oic acid, 2α,3α,19α,23-tetrahydroxyurs-12-en-28-oic acid, 19α-hydroxylurs-12-en-28-oic acid, clethric acid, 3β-(trans-p-coumaroyloxy)-2α,23-dihydroxyurs-12-en-28-oic acid, 3-oxo-ursolic acid, 3-oxo-19α,23,24-trihydroxyurs-12-en-28-oic acid, 19,24-dihydroxyurs-12-en-3-one-28-oic acid | [8] |
| Lupane | Betulinic acid, 3-epi-betulinic acid | [30] |
| Oleanane | Oleanolic acid | [30] |
| Cycloartane | Cycloartenol, cycloeucalenol, O-acetyl-delta24 cycloartenol, cycloartenol acetate | [754, 828] |
| Miscellaneous | β-amyrin, α-amyrin, γ-amyrin, β-sitosterol, stigmasta-5,22-dien-3-ol, lupeol, ligudentatin A, liguhodgsonal, oplopanone, pomolic acid, taraxerol, 8β-ethoxyeremophil-3,7(11)-diene-8α,12(6α,15)-diolide, taraxerene, neohop-13(18)-ene, diploptene, 28-norolean-17-en-3-one, lantadenes A/D/C, icterogenin, pomonic acid, lantabetulic acid | [589, 729, 826, 968, 1101, 1137] |
Triterpenoids are abundant in diverse natural sources. E. urograndis, E. grandis, and E. maidenii barks contain major components like ursolic acid (1.9–3.6 g/kg), betulinic acid (1.3–2.1 g/kg), and oleanolic acid (0.8–1.4 g/kg) [30]. E. dendroides latex has triterpenes as the largest class (79.53%), dominated by cycloartenol (21.36%) and cycloeucalenol (14.36%) [33]. S. terebinthifolia dichloromethane fraction features triterpenes including 28-norolean-17-en-3-one (29.18%), lupenone (8.04%), and lupeol (9.08%) [121]. Trichoderma viride mycelia crude extract has a total triterpene content of 38.34% (wt/wt) [264], while M. americana L. bark extract contains 0.21% triterpenes [265]. Triterpenoids are also present in flower enfleurage extracts (≈10% from day 4 onwards) [266], Callyspongia genus metabolites [269], Lantana species (pentacyclic triterpenoids) [122], and licorice (e.g., glycyrrhizic acid) [270]. Four triterpenoids were identified in a phytoconstituent analysis [271].
Structural Classification and Skeletal Diversity of Triterpenoids from Fungal and Plant Extracts
Terpenoids typically occur as complex mixtures, extractable from natural sources via techniques like steam distillation (for mono- and sesquiterpene-rich essential oils) or successive solvent extraction with increasing polarity—often using Soxhlet or maceration with dried, ground plant material [131]. Careful handling during extraction and isolation is critical to avoid artefact formation [131]. Purification for structural elucidation, biological testing, or pharmaceutical use relies on chromatographic methods including column chromatography, preparative HPLC, and radial chromatography; complex mixtures like essential oils benefit from preparative HPLC- and GC-mass spectrometry [131]. For instance, further purification of fractions with hexane–EtOAc mixtures isolated triterpenoids such as taraxerol acetate, taraxerol, friedelan-3β-ol, euphol, lanosta-8-en-3β-ol, lanosta-24-en-3β-ol, lanosta-5-en-3β-ol, friedelin, and 30-nor-hopan-3β-ol-22-one [272].
Triterpenoid Extraction and Enrichment Outcomes
| Technique/Method | Parameter/Substance | Result | Citation |
|---|---|---|---|
| Response Surface Methodology (RSM) | Optimization of extraction parameters (time, ultrasonic power, liquid-to-solid ratio, temperature) | Maximum triterpenoid yield: 18.3751 mg/g | [273] |
| Macroporous Adsorption Resins (MARs) | HPD-600 resin for triterpenoid enrichment | Yield: 75.48%; final content: 129.28 mg/g | [274] |
| Ultrasonic Extraction (USE) vs. Soxhlet Extraction (SE) | Inotodiol yield in Inonotus obliquus (chaga) using chloroform (Chl), cyclohexane (Chex), petroleum ether (Pe), hexane (Hex) | USE yielded more phytosterols and triterpenoids than SE; higher inotodiol with Chl, Chex, Pe, Hex | [99] |
| Solvent type (ethyl acetate) | Inotodiol in chaga extracts | Inotodiol prevailed in ethyl acetate extracts | [99] |
| Chaga body size | Betulin accumulation | Dependent on chaga body size; concentrated in inner fungal parts of birch trunk-derived chaga | [99] |
| Chloroform extraction | Lanostane-type triterpenoids (nonotsuoxodiol B, inonotsuoxodiol C, epoxyinonotsudiol, methoxyinonotsutriol) in chaga | Identified via LC–MS or NMR | [99] |
Structural elucidation of isolated terpenoids prioritizes spectroscopic methods to avoid artefacts from chemical treatments [131]. A combination of 1H/13C NMR spectra and 2D NMR experiments (COSY, TOCSY, NOESY, HSQC, HMBC) determines structure and relative stereochemistry [131], while X-ray diffraction confirms structures for crystalline compounds—e.g., tricholimbrin E (C30H48O4) [275] and ten undescribed lanostane/cycloartane-type triterpenoids (schipropins A–J) from S. propinqua [126]. Absolute configuration is established via X-ray analysis (for heavy-atom-containing molecules), chiroptical data (optical rotatory dispersion, circular dichroism), chemical correlation, racemate resolution, Mosher’s NMR methods, or enzymatic reactions [131]. For example, ECD calculations determined the absolute configuration of ursane-triterpenoids (compound 1: 3S,5R,8R,9R,10S,11R,14S,17S,18S,19S,20R; compound 2: 3S,5R,8R,9R,10R,14S,18S,19S,20R) [124] and lanostane triterpenes (tricholimbrin A: 3R,5R,9R,10S,13R,14S,16S,17R,20R; tricholimbrin B: 3R,5R,9R,10R,13R,16S,17R,20R) [275]. Triterpenoid standards from fungal sources (e.g., Antrodia cinnamomea) undergo full structural characterization via NMR and MS, with purity confirmed by HPLC [103]. Identities may also be verified using commercial standards or libraries of trimethylsilylized natural compounds [276]. For instance, ursolic acid (3β-hydroxyurs-12-en-28-oic acid) was identified via 1H-NMR signals (two doublet secondary methyl groups at δ0.98 and δ1.00, five tertiary methyl groups, a trisubstituted olefinic double bond at δ5.52, and an oxymethine proton at δ3.44) matching literature data [277]. Lupeol (C30H50O) was detected in RCSC fractions via MS (mass: 426.39) [278] and alongside ligudentatin A, ursolic acid, and oleanolic acid in other extracts using 1H/13C-NMR comparison with literature [279]. Glycyrrhizic acid (a triterpenoid saponin from Glycyrrhizae Radix) was identified via LC–LTQ–MS–MS, with its [M + H]+ ion (m/z 823.4086) losing two gluconic acid moieties to form fragments at m/z 647.3788 and 471.3457 (the latter further losing H2O to m/z 453.3356) [130].
Sesquiterpenoids encompass diverse classes: pseudoguaianolide-type sesquiterpene lactones (e.g., confertdiolide), omphalane-skeleton compounds (e.g., omphalic acid) [131][8], guaianolides (e.g., 2α,4α-dihydroxy-7αH,8αH,10αH-guaia-1(5),11(13)-dien-8β,12-olide) [280], eudesmane- and guaiane-type compounds from resinous exudates [280], and ar-tumerone from Ganoderma lucidum extracts [281]. Quantitative analysis reveals varying proportions: 4.3% sesquiterpenes and 5.18% oxygenated sesquiterpenes in ethanolic bark extracts of M. americana L. [265]; 3.75% sesquiterpenes (with β-cedrene as most abundant) in E. dendroides latex [33]; and 16.06% sesquiterpenes (spatulenol: 2.22%, β-caryophyllene: 2.08%, caryophyllene oxide: 1.66%, α-eudesmol: 1.36%) in S. terebinthifolia residues [121]. Sesquiterpenoids may also appear in trace amounts alongside triterpenoids in enriched fractions, as observed in UPLC-Q-TOF-MS analysis of Inonotus hispidus extracts [274]. Metabolomic mass profiling of Lantana extracts via Global Natural Product Social Molecular Networking (GNPS) identified sesquiterpenoids, including α-humulene in L. montevidensis and copaenol (first reported in Lantana) [122].
Triterpenoids exhibit diverse skeletal classes across plant and fungal sources:
- Plant-derived: Dammarane-type (e.g., 3-OH dammarane derivatives), norursane-type (e.g., 24-norursane triterpenes) [8][30][282][132], ursane-type (e.g., ursolic acid, 28-nor-urs-12-ene-3β,17β-diol) [124][283], oleanane-type (e.g., oleanolic acid, methyl Commate B) [124][284][283], lupane-type (e.g., betulinic acid, lupeol) [285][283], hopane-type (e.g., 30-nor-hopan-3β-ol-22-one) [272], cycloartane-type [280], and triterpenoid saponins (e.g., zygophyloside K, zygophyloside G) [286].
- Fungal-derived: Predominantly lanostane-type (e.g., G. lucidum’s ganoderic acid derivatives, lucidadiol [123][287][288]; tricholimbrin A and B [275]), including ganoderic acids C2, C6, G, B, A, E, and 7β,12β-dihydroxy-3,11,15,23-tetraoxo-lanost-8-en-26-oic acid [288]. I. obliquus extracts feature ergosterol, lanosterol, inotodiol, trametenolic acid, and betulin [99], with lanostane-type triterpenoids prominent [99][106].
- Species-specific profiles: Ganoderma species produce diverse lanostane-type triterpenoids (G. lucidum: 40 ganoderic acids, 14 ganoderiols, 5 ganolucidic acids, 15 lucidenic acids [106]; G. tsugae: ganoderic acids E, C5, C6, G, ganoderenic acid D [106]; G. applanatum: 3β,7β,20,23n-tetrahydroxy-11,15-dioxolanosta-8-en-26-oic acid [106]; G. pfeifferi: lucialdehyde D, ganoderone A, ganoderone C [106]). PHE (gum resin extract) contains ursane (α-amyrin, brein, ursolic acid), oleanane (β-amyrin, maniladiol, oleanolic acid), and tirucallane (elemonic acid) classes, with nonacidic triterpenoids (NATs) and acidic triterpenoids (ATs) comprising over 28% and 39% of total composition, respectively [289]. S. terebinthifolia features lupeol (16.32%), lupenone (12.75%), and 28-norolean-17-en-3-one (10.69%) [121]; C. paliurus leaves include arjunolic acid, cyclocaric acid B, and oleanolic acid [290]; YPG contains 72 tentatively identified terpenoids, with triterpenoid saponins concentrated in Lonicera Japonica Thunb, Puerariae Lobatae Radix, and Glycyrrhizae Radix [130]; Lantana species have lantadenes A/D/C, icterogenin, and pomonic acid, with amyrin and lantabetulic acid exclusive to L. montevidensis [122].
Triterpenoids are widely distributed in plant and fungal extracts: 4 triterpenoids were identified in plant extract phytoconstituent analyses [271]; triterpenes/steroids were detected in M. americana L. bark [265], propolis [291][34], R. mangle leaves [276], and E. dendroides latex (79.53% of identified compounds) [33]. Fungal sources include A. cinnamomea (dehydroeburicoic acid, dehydrosulphurenic acid, antcins [103]; strain SH-18: 19.12 ± 0.31 mg/g triterpenoids [274]) and G. oerstedii (maximum total triterpenoid content: 686±21 µg/ml after 9 days of culture [292]). Profiles vary by source: natural and cultivated A. cinnamomea fruiting bodies have comparable profiles but different contents, while fermented broth lacks triterpenoids [103]; propolis types YCP A (higher non-acetylated triterpenols: cycloartenol, lupeol, β-amyrin) and YCP B (enriched in acetylated derivatives: lupeol acetate, β-amyrin acetate) differ in composition [34]; I. obliquus from France is suitable for betulin/betulinic acid production, while Canadian chaga is ideal for inotodiol [99]. Key triterpenoid concentrations in chaga range from 0.04–22.0 mg/100 g (ergosterol), 1.05–112 mg/100 g (lanosterol), 1.5–112 mg/100 g (inotodiol), 0.60–6.82 mg/100 g (betulin), and 0.42–7.10 mg/100 g (trametenolic acid) [99]. Birch-origin chaga has similar triterpenoid/sterol compositions (ergosterol, lanosterol, inotodiol, betulin, trametenolic acid, low stigmasterol), while alder-origin chaga has higher concentrations [99]; oat-grown chaga lacks chaga-specific triterpenoids [99]. C. paliurus ethanol extracts show geographical variation (highest: Wufeng, 8.15 mg/g; lowest: Anji aqueous, 0.05 mg/g [290]); bitter gourd cultivars CB, LJ, and LBS have higher total triterpenoid content (TTC) than PG and JLZ [293]. Triterpenoids were also detected in olive leaf samples [294], C. forskohlii ethanol root extracts (including betulin) [295], and methanol extracts of P. curviflorus shoots, S. lappa roots, and C. glomerata [296].
Detection of triterpenoids uses phytochemical screening with reagents like ferric chloride, n-butanol-HCl, cerric sulphate [297], and Lieberman Burchard reagent [298]. Qualitative TLC tests use toluene–chloroform–ethanol (40:40:10) as mobile phase, lupeol as a standard, and anisaldehyde–sulfuric acid for detection [285]. GC-MS reveals triterpene presence [299][300], including triterpene ester metabolites in Lantana camara leaf essential oil [262]. Additional methods include FTIR (identifying hydroxyl, enol, and benzene rings [273][292]), histochemistry (localizing triterpenes in plant tissues [301]), and tests like Salkowski (yellow lower layer), Liebermann-Burchard (deep red), Zimmermann (violet for 3-oxo triterpenoids) [302], and a modified chloroform-concentrated H2SO4 test (reddish brown coloration [303]). C. moschata seed extracts were analyzed via TLC with chloroform/methanol (95:10) and vanillin–sulfuric acid [260]; the Liebermann reaction (violet to blue-green) and Carr and Price reaction (fleeting blue to blue violet) screen for triterpenoids [304]; Libermann–Burchard tests detect triterpenoids in methanolic extracts [296]; and GNPS-based metabolomic profiling identified triterpenoids in Lantana, with five parent ions matching pentacyclic triterpene standards in L. camara [122].
Quantification methods include UV-visible spectrophotometry (ursolic acid as standard for total triterpenes [287]) and UPLC-Q-TOF MS (quantifying ursolic, oleanolic, and betulinic acids in old apple cultivars: 466.3–3753.6 µg/g dm [283]). A. cinnamomea triterpenoid standards use calibration curves (e.g., methyl antcinate B, dehydroeburicoic acid) for content calculation [103]. Propolis total triterpenoid content ranges from 6.8–21.4 μg/100 μg (YCP A) and 2.4–12.8 μg/100 μg (YCP B) [34]. Bitter gourd TTC is determined via ethyl acetate extraction, sonication, filtration, perchloric acid/vanillin–glacial acetic acid treatment, and absorbance measurement at 555 nm [293]. Olive leaf triterpenoids (oleanolic, ursolic, maslinic acids) use species-specific calibration curves [294]; total triterpenoids vary significantly (p < 0.05) by sampling time (highest: November [18.8 mg/g], August [27.4 mg/g]; absent in April; January: 0.1–11.9 mg/g) and sample type (fresh August samples highest [294]).
Structural identification leverages multiple techniques: HRESIMS provides molecular formulae (e.g., C32H52O4 [124], C31H44O7 [275], C44H78O3 [272]); IR detects functional groups (hydroxyl, ester, carbonyl, olefinic [275][272]); 1D/2D NMR confirms frameworks and substituent positions (HMBC identified ethoxyl/carboxyl groups in an ursane-triterpenoid [124], a γ-lactone ring E in a lanostane triterpene [275], and C-3 esterification in lanost-24-en-20-ol-3-tetradecanoate [272]); NOESY/ROESY determines stereochemistry (β-H-11 [124], α-H-16/H-17/H-20 and 14-OOH [275], β-H-14/H-20 [275]). MS (ESI-MS, MS2) aids identification via literature/standard matching (e.g., G. lucidum ganoderic acids with H2O/CO2 neutral losses [288], Boswellia serrata resin triterpenoids [284]). GC-MS identifies triterpenoids like taraxerol, β-amyrin, and oleanolic acid in R. mangle leaves [276], and cycloartenol/cycloeucalenol acetates in E. dendroides latex [33]. UPLC-MS/MS and GC-MS enable high-throughput identification (153 terpenoids detected in one study [270]); chaga lipid fractions [99] and PHE composition (13 triterpenoids [289]) were analyzed via GC/LC-MS. UHPLC-HRMS identified triterpenes for the first time in Pseudobombax ellipticum [136]; GC-MS detected betulin in C. forskohlii ethanol root extracts [295] and beta-Amyrin in plant extracts [305]; LC–LTQ–MS–MS and molecular networking tentatively identified 37 terpenoids (including pentacyclic triterpenes) in Lantana [122].
Analytical Methods for Detection and Quantification of Terpenoids in Complex Matrices
Phytochemical screening is a foundational step for terpenoid detection, with colorimetric tests adapted to specific terpenoid classes and thin layer chromatography (TLC) used for confirmation. Advanced analytical techniques enable detailed characterization, while spectrophotometric methods quantify triterpenoids, and macroporous resin chromatography supports purification. Triterpenoid profiles in complex matrices vary by sample origin, structure, and external factors.
Colorimetric Tests for Terpenoid Detection and Differentiation
| Test Name | Reagents/Protocol | Indication (Color/Result) | Target Terpenoid Class/Specificity | Citations |
|---|---|---|---|---|
| Liebermann Burchard | Anhydrous acetic acid + concentrated sulphuric acid | Red precipitation (triterpenoids); deep red (triterpenoids); brown ring + green upper layer (steroids) | Triterpenoids; differentiates triterpenoids from steroids | [306], [302] |
| Salkowski | Extract + chloroform + concentrated sulfuric acid | Reddish-brown interface/layer (terpenoids); yellow lower layer (triterpenoids); red lower layer (steroids) | Terpenoids; differentiates triterpenoids from steroids | [307][308][309][310][311][312][313], [302] |
| Zimmermann | m-dinitrobenzene + alkali | Violet color (fades on dilution) | 3-oxo steroids and triterpenes | [302] |
| Liebermann Reaction | 1 ml extract + 0.2 ml acetic anhydride + 4 drops concentrated H₂SO₄ | Color change from violet to blue-green | Triterpenoids | [304] |
| Modified Liebermann–Burchard (50 mg sample) | Reagent with 50 mg sample | Purple/red (terpenoids); green/blue (steroids) | Differentiates terpenoids from steroids | [314] |
TLC Protocols for Terpenoid Confirmation
| Migration System | Spraying Reagent(s) | Detection Method | Indication (Color/Fluorescence) | Target/Application | Citations |
|---|---|---|---|---|---|
| N/A (methanol extracts) | Vanillin-sulphuric acid or Liebermann-Burchard | UV-366 nm or visible light | Characteristic colors and fluorescences | Terpenoid presence in certain plant methanol extracts | [315], [316][317] |
| N/A | Modified Liebermann–Burchard | N/A | Dark green to bluish-green | Triterpenes/steroids | [318] |
| Chloroform/methanol (95:10, v/v) | Vanillin–sulfuric acid; vanillin–phosphoric acid | N/A | Triterpen spots (vanillin–sulfuric acid); blue-violet/brown cucurbitacin spots (vanillin–phosphoric acid) | Triterpenoid-specific analysis; identifies cucurbitacin B glucoside (Rf≈0.29) and aglycone (Rf≈0.9) in Cucurbita moschata seed methanol extracts | [260] |
Spectrophotometric Methods for Triterpenoid Quantification
| Plant/Sample | Method Protocol | Reference Standard | Absorbance Wavelength | Result | Citations |
|---|---|---|---|---|---|
| K. indica | Using oleanolic acid as reference | Oleanolic acid | N/A | Total triterpenes (TTK): 17.72% | [319] |
| General (UAE) | 1 mL extract + 2 mL chloroform + 200 μL sulfuric acid; precipitate dissolved in methanol | Ursolic acid | 538 nm | Results as ursolic acid equivalents (mg UAE/g) | [320] |
| G. senegalensis | Same as above | Ursolic acid | 538 nm | Total terpenoid content (TTC): 46.27–51.6 mg UAE/g (highest in stems) | [320] |
| B. appendiculata | 1 mL 2% vanillin + 100 mg/mL extract in methanol; ice bath agitation; 60 °C incubation | N/A | 608 nm | Acetone extracts: 115.67 ± 1.04 mg/g (highest) | [321] |
| Asparagus racemosus Willd | 5% w/v vanillin acetic solution + sulfuric acid; 70°C for 30 min | Ursolic acid | 573 nm | Ethyl acetate: 109.8 ± 5.6 mg/g; aqueous: 95.6 ± 7.5 mg/g (dry weight) | [322] |
| Leaf sample | 10 mg in 1 mL methanol + 100 μL 5% vanillin-glacial acetic acid + 500 μL perchloric acid; 60 °C for 45 min | Ursolic acid | 548 nm | N/A | [323] |
| Bitter gourd | 0.1 g powder sonicated with ethyl acetate; 1.2 mL perchloric acid + 500 μL 5% vanillin–glacial acetic acid; 70 °C for 15 min; 160 μL acetic acid added | N/A | 555 nm | N/A | [293] |
| Olive leaves | Oleanolic acid (oleanolic/ursolic acid); maslinic acid (maslinic acid) | Oleanolic acid; maslinic acid | N/A | Seasonal variation: August (27.4 mg/g), November (18.8 mg/g), near-absence in April | [294] |
Advanced Analytical Techniques for Terpenoid Characterization
| Technique | Application | Key Findings | Citations |
|---|---|---|---|
| UPLC-Q-TOF-MS | Qualitative triterpenoid enrichment analysis | Tentatively identified 4 triterpenoids (e.g., Olibanumols J); trace sesquiterpenoids, diterpenoids, alkaloids | [274] |
| UHPLC-HRMS (± modes) | Metabolic profiling of Pseudobombax ellipticum leaves, bark, flowers | First report of triterpenes in the species | [136] |
| GC-MS | I. obliquus extracts (solvent/extraction technique effect) | Dominant triterpenoids: inotodiol, lanosterol, betulin, trametenolic acid; inotodiol (ethyl acetate), betulin (birch trunk chaga) | [99] |
| GC-MS | S. terebinthifolia dichloromethane fraction | Major: pentacyclic triterpenes (lupeol, lupenone, 28-norolean-17-en-3-one), squalene; monoterpenes (p-cymene, limonene), sesquiterpenes (spatulenol, β-caryophyllene); acid triterpenes (masticadienoic acid, schinol), glycoside triterpenes | [121] |
| HPLC-PDA (252 nm) | CVme extracts | UV spectra characteristic of terpenoids | [324] |
| HPLC-UVD | C. paliurus extracts (Waters system, X-Bridge C18 column, gradient elution) | 6 triterpenoids identified (e.g., arjunolic acid); TTC: 8.15 mg/g (Wufeng ethanol) to 0.05 mg/g (Anji aqueous) | [290] |
| HPLC-ELSD | Ginkgo biloba total triterpenoid lactones (TTLs) | Soxhlet extraction (ethyl acetate + 2% HCl); Accucore™ XL C18 column; mobile phase: methyl alcohol:THF:water (20:8:72) | [211] |
| ESI + APPI MS | Terpenoid analysis | Complementary data; APPI targets non-polar/semi-polar neutral terpenoids | [325] |
| Tandem-MS (QC samples) | Triterpenoid identity confirmation in complex matrices | Confirms identities | [326] |
| GNPS (LC–LTQ–MS–MS) | L. camara and L. montevidensis extracts | 37 terpenoids tentatively identified (pentacyclic triterpenes, sesquiterpenes like α-humulene); new copaenol sesquiterpene in genus | [122] |
| GC–MS | Plant extracts | Identifies triterpenoids (e.g., beta-Amyrin) | [305] |
| MS | YPG samples | 72 terpenoids tentatively identified; triterpenoid saponins in Lonicera Japonica, Puerariae Lobatae Radix, Glycyrrhizae Radix; glycyrrhizic acid characterized via [M + H]+ (m/z 823.4086) and fragments | [130] |
Macroporous Resin Chromatography for Triterpenoid Purification
| Plant/Sample | Resin Type | Key Parameters | Result | Citations |
|---|---|---|---|---|
| K. indica | HDP-500 | Flow rate 0.02 g/ml, sampling mount 2 ml/min, 70% ethanol elution (2 BV) | Yield: 64.86 g TTK | [319] |
| I. hispidus | HPD-600 | Adsorption 68.26%, desorption 88.24%; pseudo-second-order model (theoretical 5.92 mg/g vs. actual 5.27 ± 0.13 mg/g); 70% ethanol desorption (94.55 ± 0.21%) | Triterpenoid content: 129.28 mg/g; yield: 75.48% (highest reported) | [274] |
Triterpenoid profiles in complex matrices vary by sample origin: I. obliquus from France suits betulin/betulinic acid production, while Canadian chaga is ideal for inotodiol, with alder-origin samples having the highest total triterpenoid/sterol content (0.42–112 mg/100 g) [99]. Fungal strain SH-18 had a triterpenoid content of 19.12 ± 0.31 mg/g, higher than other strains [274]. In W. cocos, triterpenoid biosynthesis correlates with sterol synthesis, membrane maintenance, and transport, linked to erg11 and FDPS genes [218]. Cannabis terpenoid profiles vary by plant part: mono- and sesquiterpenoids (0.125–0.278% leaves, 1.283–2.141% inflorescences; β-caryophyllene most abundant at 6.71–45.25%), and triterpenoids (β-amyrin, epifriedelanol, friedelin) increasing from inflorescences (not detected) to roots (0.1–0.3%) [327]. Birch bark extractives include betulin, betulinic acid, lupeol, and degradation products [325]. Histochemical analysis with p-anisaldehyde/H₂SO₄ detected triterpenoids in leaf scales forming a protective cover [328]. Olive leaf triterpenoids vary by freshness/drying temperature, with highest values in fresh August samples [294]. Sisal terpenoids show annual (2018–2019 > 2017–2018) and geographical variation (e.g., 2.539 mg UA/g in Khushab autumn 2018) [323]. G. biloba TTLs are highest in roots, with MeJA treatment increasing content by 60.15% [211]. Lantana species have pentacyclic triterpenoids (lantadenes A/D/C); amyrin and lantabetulic acid are exclusive to L. montevidensis [122]. In milk, plant terpenoids transfer directly but may degrade/modify via rumen bacteria [326]. Non-polar n-hexane and semi-polar ethyl acetate extract terpenoids/steroids; TCEA and TCH extracts contain terpenoids, with steroids only in TCH [314].
Comparative Content Analysis of Sesquiterpenoids and Triterpenoids Across Species and Environmental Conditions
Terpenoid Extraction, Isolation, and Analytical Methods
Terpenoids occur as complex mixtures, with essential oils (mono- and sesquiterpenes) extracted via steam distillation, while general terpenoid extraction from plant materials uses successive solvent extraction or liquid/liquid partition from acetonic or alcoholic extracts (with artefact avoidance) [131]. Sesquiterpenoid isolation employs techniques including MPLC (RediSep SiO₂ and C₁₈), silica gel column chromatography, cycling HPLC, SFE, HSCCC, and UFLC-MSn coupled with HR-MS; structural elucidation relies on TLC, IR, UV, EI-MS, HR-ESI–MS, MALDI-TOF MS, FAB-MS, HR-DART-MS, 1D/2D NMR (¹H NMR, ¹³C NMR, DEPT, HMBC, HSQC, ¹H-¹HCOSY, ROESY, NOESY), ECD, and X-ray crystallography [134]. Triterpenoid quantification uses methods like the vanillin-acetic acid method (expressed as mg ursolic acid per g substrate dry weight) [329][330][323] and the external standard method (calibration curves) [331][294].
Preparative TLC (chloroform/methanol 97:3, v/v) fractionates triterpenic acids (Rf 0.2–0.3) and steroids/neutral triterpenes (Rf 0.3–0.9) [332], while TLC also differentiates fungal crude drugs (e.g., "Lingzhi" [Ganoderma lucidum]) via unique triterpene patterns [106]. Additional analytical methods include GC–MS for sesquiterpenoid and triterpenoid structural identification in coal samples [300] and plant residues [121], and GC-MS/FID for triterpenoid identification/quantification in bilberry fruits and leaves [333]. UPLC-Q-TOF MS (ESI negative mode) identifies/quantifies ursolic, oleanolic, and betulinic acids in apple cultivars [283], while NMR and MS characterize triterpenoid standards from fruiting bodies [103] and classify yellow Cuban propolis (YCP) into Type A/B via ¹H/¹³C NMR signals [34]. Triterpenoid identities are confirmed using commercial standards, trimethylsilylized compound libraries [276][327], and a tandem-MS approach with condition-specific QC samples [326]. Salkowski’s test enables qualitative terpenoid detection [334].
Sesquiterpenoid Profiles and Biological/Environmental Effects
Sesquiterpenoids include pseudoguaianolide-type sesquiterpene lactones (e.g., confertdiolide, anti-inflammatory) and eudesmane-skeleton sesquiterpenes (e.g., eudesm-6-en-4β-ol, guai-6-en-10β-ol) in Guarea guidonia leaf volatile oil [131][12]. In seedling foliage, sesquiterpenoid (SQT) emission accounts for 1.2% of total terpenoid emission (eight compounds), with (E)-β-farnesene and α-humulene emitted in trace amounts by intact seedlings [335]. Weevil feeding damage increases lower stem bark SQT emissions (29.4 ± 19.6 ng g(DW)⁻¹ h⁻¹ control vs. 208.0 ± 71.9 ng g(DW)⁻¹ h⁻¹ damaged) [335], boosting longifolene/δ-cadinene emissions and inducing α-copaene/α-humulene detection [335].
In cannabis resin, sesquiterpenes (isocaryophyllene, β-caryophyllene, α-bergamotene, α/β-humulene) undergo evaporative losses; β-caryophyllene shows greater relative losses due to aerial oxidation of its strained E-configuration [336]. Its oxidation product, caryophyllene oxide, partially compensates for losses in air-exposed samples but undergoes anaerobic degradation in airtight samples [336]. Twig sesquiterpene concentration varies with resistance across forest sites [337], while bark beetle attacks reduce longipinene (55%)/β-bourbonene (96%) emissions, eliminate α-humulene/germacrene-D/γ-cadinene/unidentified SQTs, and induce (E,E)-α-farnesene [338].
Major sesquiterpenes include (E)-β-caryophyllene (40.8%), α-humulene (21.2%), germacrene D (6.9%), and bicyclogermacrene (7.9%) in Lantana camara leaf essential oil [262]; α-cyperone, β-selinene, and nootkatone (anti-inflammatory) in C. rotundus [134]; ar-tumerone (9.58%) in G. lucidum ultrasonic-assisted ethanol extracts [281]; and nerolidol (4.49%), α-elemene (1.38%), and δ-cadinene (1.13%) in M. americana bark extracts [265]. In Trichoderma viride mycelia, sesquiterpenes constitute 34.07% of volatile compounds (cyclooctanol, caryophyllene oxide, α-bisabolol as major components) [264]; in E. dendroides latex, they represent 3.75% (b-cedrene 1.17% most abundant) [33].
Sesquiterpenoid release increases during flower development (detected day 4, higher by day 7) [266]. They are more abundant in gibberellic acid (GA₃)-treated plant extracts than benzyladenine (BA)-treated or control (MS₀) samples [241], with coronopilin (the only terpene in LE) most intense in GA₃-treated LE [241]. In ZY cultivar leaves, sesquiterpenes are the main terpenoids (elemene highest content) [339]; in cannabis fan leaves, their total content exceeds monoterpenoids in Chemovar I/II (β-caryophyllene 6.71–45.25% most abundant) [327]. Plant residues contain sesquiterpenes (16.06%) including spatulenol (2.22%), β-caryophyllene (2.08%), caryophyllene oxide (1.66%), and α-eudesmol (1.36%) [121]. Sesquiterpene hydrocarbons (low concentration) include β-caryophyllene, germacrene D, β-cubebene, β-elemene, and β-cadinene [340]; rose species show varying total content: R. gallica (7.0%) > R. centifolia (5.2%) > R. alba (2.1%) > R. damascena (0.6%) [340].
Triterpenoid Profiles and Biological/Environmental Effects
Triterpenoids include dammarane-type (3-OH derivatives), norursane-type, and ursane-type (ursolic acid) compounds (identified via HRESIMS, IR, NMR) [8], with oleanonic acid, lupeol, and ursolic acid exhibiting anti-inflammatory activity [131]. In Eucalyptus, hydrolyzed lipophilic extracts of E. urograndis/E. grandis are dominated by triterpenoids (betulinic, ursolic, oleanolic acids; β-sitosterol abundant) [30]. Eucalyptus outer bark extracts have ursolic acid (1.9–3.6 g/kg) as most abundant, followed by betulinic acid (1.3–2.1 g/kg) and oleanolic acid (0.8–1.4 g/kg) [30]; E. urograndis/E. maidenii outer bark contains a lupane-type triterpenic acid (0.7–1.2 g/kg, possibly 3-epi-betulinic acid) [30].
Blueberry fruit cuticular waxes have major triterpenoids (β-amyrin, α-amyrin, ursolic acid, oleanolic acid, lupeol, betulinic acid), with β-amyrin most abundant (35.44% ‘Baldwin’, 23.03% ‘Garden Blue’) [331]. Their content peaks at day 14 (62.18%/72.18% of total wax in controls) [331], with MT treatment increasing ‘Baldwin’ content but decreasing ‘Garden Blue’ content during storage [331]. Apple cuticular waxes are dominated by ursolic/oleanolic acids, with minor triterpenic acids varying by cultivar (betulinic acid in ‘Redkroft’, pomolic acid in ‘Ligol’) [332]; leaf triterpenoid levels are ~10x lower than fruits [332]. Citrus flavedo extracts contain triterpenoids (5.2–7.6% of total compounds: β-sitosterol acetate, β-sitosterol, stigmastan-3-5-diene) [65].
Apple bagasse total triterpenes increase during solid-state fermentation, reaching 26.440 ± 0.949 mg ursolic acid/g substrate dw in aqueous extracts at 28 days [329]. Lantana camara triterpene ester metabolites (lantadenes) cause photosensitization/intrahepatic cholestasis in small ruminants [262]. Additional triterpenoids include methyl Commate A (boswellic acids), methyl Commate B (oleanolic acid), and methyl Commate C (sulfurenic acid) in Boswellia serrata resin [284]; α-amyrin, β-amyrin, taraxerol, and oleanolic acid from leaf acid depolymerization [276]. Old apple cultivars have triterpenoid content 466.3–3753.6 µg/g dm (ursolic acid 32–96% most abundant, followed by oleanolic acid 2–20% and betulinic acid 1–14%) [283]. Pear peel has higher oleanolic acid (164.3–3066.6 lg/g DW) than ursolic acid (125.6–791.2 lg/g DW) across cultivars, with peel content 4–16x higher than flesh [333].
E. dendroides latex triterpenes represent 79.53% of identified compounds (cycloartenol 21.36%, cycloeucalenol 14.36%, O-acetyl-delta24 cycloartenol 9.39%, cycloartenol acetate 5.40% major) [33]; M. americana bark extracts have 0.21% triterpenes [265]; Trichoderma viride mycelia have 38.34% total terpenes (including triterpenoids) [264]. Antrodia cinnamomea (AC) triterpenoid profiles vary by geography, cultivation, and manufacturing, with natural fruiting bodies having more triterpenoids than cultivated products [103]. Bog samples have triterpenes as dominant alicyclic hydrocarbons (taraxerene, neohop-13(18)-ene, diploptene) [104]. YCP Type A samples have triterpenic alcohols (β-amyrin, lupeol, cycloartenol, 9,19-cyclo-lanostan-3β-ol-24-methylene) and 0–35% acetyl derivatives; Type B has 48–57% acetylated derivatives (lupeol acetate, β-amyrin acetate) [34].
BA-treated plant extracts have more triterpenoids than GA₃/MS₀ extracts [241]. C. paliurus leaf triterpenoids (arjunolic acid, cyclocaric acid B, pterocaryoside A) vary by location, with ethanol extracts having higher content than aqueous extracts [290]. Olive leaf triterpenoids (ursolic, oleanolic, maslinic acids) peak in August (27.4 mg/g) and November (18.8 mg/g) [294]. Cannabis triterpenoid content (β-amyrin, epifriedelanol, friedelin) increases from inflorescences (not detected) to roots (0.1–0.3%), with friedelin most prominent in stem barks/roots [327]. Plant residues have triterpenes dominating GC–MS chromatograms (45–54 min): 28-norolean-17-en-3-one (29.18%), lupenone (8.04%), lupeol (9.08%), β-sitosterol (11.29%) [121].
Triterpenes are diverse plant natural products with roles in surface waxes, membranes, and signalling, and exhibit antioxidant, anticancer, and antibacterial activities [340]. Rose species contain lupeol, α-amyrin, β-amyrin, oleanolic acid, ursolic acid, carotenoids, and tocopherols [340]; CO₂ extracts have 8 triterpenes, with lupeol (1.2% R. damascena, 0.7% R. gallica) and β-amyrin (0.9% R. gallica, 0.5% R. damascena) most abundant; total content ranges 2.7% (R. gallica) to 0.4% (R. alba) [340].
Comparative Terpenoid Profiles and Environmental/Organ-Specific Variations
Comparative analysis reveals species-specific terpenoid markers: Andalusian sparkling wines are discriminated by 8 monoterpenes and 2 sesquiterpenoids (TDN, Megastigma 6Z8E), while Cavas have cis-geraniol [341]. Codonopsis triterpenoids (oleanolic acid, echinocystic acid) are more abundant in leaves/stems than roots [342]. ‘Bingtang’ fruit intracuticular wax triterpenoids (β-amyrin, lup-20(29)-en-3-one) vary with storage: higher total content at 25°C (peaking day 20) vs. 4°C (increasing over 40 days via squalene accumulation) [263].
Environmental conditions influence terpenoid content: Grignolino berry levels correlate with optimal early development temperatures [343]; drought stress/nanosilicon affect hemp essential oil sesquiterpene content [344]; polyhouse-grown Shankhapushpi has higher triterpenoid content (11.1 ± 0.4 mg UAE g⁻¹E methanolic extract) than open-field samples (1.7 ± 0.1 mg UAE g⁻¹E aqueous extract) [330]. Daucus carota green hairy roots have 2.3x higher monoterpenes and 1.3x higher sesquiterpenes than normal roots; clomazone inhibits MEP pathway-dependent terpenoid emission [160]. Cannabis guaiol, γ-eudesmol, and β-eudesmol are characteristic of Afghan C. indica [345]. Beetle-attacked trees have a higher total monoterpene (MT) to SQT ratio (458 ± 90) than controls (129 ± 17) [338].
Organ-specific variations include E. maidenii outer bark containing monoterpenes/sesquiterpenes, while E. urograndis/E. grandis outer bark is triterpenoid-dominated [30]; a species’ bark extracts have 4 triterpenes, leaf extracts 7, and seeds 5 [92]. Licorice terpenoids (sesquiterpenoids/triterpenoids) are a major metabolite class, with enriched biosynthesis pathways in certain comparisons [270]. Flower triterpenoid presence increases (10% in enfleurage extract day 4, higher by day 7) [266]. Leaf triterpenols (α-amyrin, β-amyrin, taraxerol) are more concentrated in brown/black leaves than yellow leaves [276].
Cultivar/location variations include ZY having higher total terpenoid content than WC (sesquiterpenes main in ZY, monoterpenes in WC) [339]; G. lucidum having 10x more triterpenoids than G. sinense [106]; bitter gourd CB, LJ, LBS having higher total triterpenoid content (TTC) than PG, JLZ [293]; Terminalia arjuna bark having the most terpenoid bands (19 in young bark) vs. A. latifolia, C. religiosa, P. marsupium [346].
Sisal terpenoid content showed non-significant season/location effects in 2017 but significant differences in 2018 [323]; 2019 spring had the highest concentrations, followed by 2018 autumn; Chakwal, Khushab, Rawalpindi had higher content than Faisalabad, Layyah [323]; Khushab had the highest (2.539 mg UA/g, 2018 autumn) and lowest (1.3075 mg UA/g, 2017) concentrations [323].
Terpenoids in milk: Most plant secondary metabolism terpenoids transfer directly to milk, though some are degraded/modified by rumen bacteria [326]. High terpenoid variability links to pasture diversity, grassland altitude/location, seasonal feeding (lactation stage/pasture availability), and management system [326]. Qualitative terpene assessment was positive in all solvent extracts of three plant organs (conventional/Soxhlet extraction), with no quantitative data provided [334].
Structural Elucidation Techniques for Novel Sesquiterpenoid and Triterpenoid Compounds
Terpenoid research encompasses extraction, isolation, structural elucidation, characterization of structural diversity, and quantification, with techniques tailored to compound type and research goals. Extraction of essential oils (mono- and sesquiterpenes) often uses steam distillation, while broader terpenoid extraction from plant materials employs successive solvent extraction or liquid/liquid partition from acetonic or alcoholic extracts [131]. Isolation of pure terpenoids for structural studies relies on chromatographic techniques like column chromatography, preparative HPLC, or radial chromatography, with complex mixtures (e.g., essential oils) benefiting from preparative HPLC- and GC-mass spectrometry [131].
Structural elucidation of terpenoids depends heavily on spectroscopic methods. Modern NMR techniques (1H, 13C, and 2D experiments including COSY, TOCSY, NOESY, HSQC, HMBC) enable routine determination of structure and relative stereochemistry [131]. When terpenoids are crystalline, X-ray crystallographic analysis can confirm structure and absolute configuration [114][268]. ECD calculations have also been used to determine absolute configurations of triterpenoids [124][275], while mass spectrometry reveals distinct fragmentation patterns (e.g., loss of neutral molecules, retro-Diels–Alder reactions) that aid identification [347].
Sesquiterpenoids exhibit diverse structural skeletons, with examples including chamigrane, cuparane, laurane, bisabolane, aristolane, brasilane, eudesmane, snyderane, and perforanes in the Laurencia genus [255]. Novel sesquiterpenoids with unprecedented skeletons (e.g., cinnamoid A from cadinane) have also been identified [7]. Triterpenoids include dammarane-type, norursane-type, lanostane-type, and ursane-type derivatives, with examples like oleanolic acid, lupeol, and ganoderic acids [8][123][124][288]. Monoterpene derivatives (e.g., iridoid glycosides) and diterpenoids (e.g., crocin) are additional terpenoid classes of interest [348].
Quantification of terpenoids uses techniques like GC, UPLC-Q-TOF-MS, and HPLC, often with calibration curves or standards to ensure accuracy [244][349][103][290]. Mass spectrometry (e.g., Q-TOF–MS, HRESIMS) also supports both identification and quantification, with complementary methods (ESI and APPI) targeting polar and non-polar/semi-polar terpenoids respectively [134][124][275][325].
Terpenoid Extraction, Isolation, and Analysis Applications
| Target Compounds | Source | Technique(s) | Reference(s) |
|---|---|---|---|
| 3 new sesquiterpenoids (1–3) | Dried A. sieversiana areolas | HP-20 column chromatography, HPLC | [114] |
| 20 compounds (including 2 terpenoids) | HT | UPLC-Q-TOF-MS (tentative identification) | [349] |
| 77 components (including terpenoids) | Extract | UPLC-Q-TOF-MS | [349] |
| 95 volatile compounds (61.1% terpenoid family: 18 sesquiterpenes, 11 sesquiterpene derivatives) | Essential oil | GC-MS | [261] |
| Sesquiterpenoids | — | MPLC (RediSep SiO2 and C18), silica gel column chromatography + cycling HPLC, flash chromatography (C18 columns), SFE, HSCCC, UFLC-MSn with HR-MS, pre-fractionation on silica columns + PTLC (silver nitrate precoated plates) | [134] |
| Triterpenoids | Betulinines Chemical Group | Isolation + derivatization (e.g., cyclopropanation with difluorocarbene) | [350] |
| 43 triterpenoids | Ganoderma lucidum extracts | Chromatographic separation | [123] |
| Sesquiterpene (2,7,10-bisabolantriene) and triterpenoids (taraxerol, friedelan-3b-ol, euphol, lanostane derivatives) | — | Silica gel column chromatography (hexane–EtOAc mixtures) | [272] |
| Cycloartane-type triterpenoid, aliphatic alcohol glycoside, eudesmane-type sesquiterpenoid, guaiane-type sesquiterpenoid | Resinous exudates of Commiphora opobalsamum | — | [280] |
| 15 sesquiterpenes | VOCs from Dittrichia viscosa leaves | — | [351] |
| Triterpenes (lupeol, lupenone, 28-norolean-17-en-3-one) | Dichloromethane fraction of S. terebinthifolia | GC–MS | [121] |
| Terpenoids | C. moschata seed extracts | TLC (silica gel, chloroform/methanol 95:10, vanillin–sulfuric acid reagent) | [260] |
| 37 terpenoids (pentacyclic triterpenoids, sesquiterpenes) | Lantana species | LC–LTQ–MS–MS, molecular networking | [122] |
| Configuration of C4 stereocenter in selin-7(11)-en-4-ol | Mutant sesquiterpene synthase product | 2D NMR spectra analysis | [244] |
| 4,5-seco-pyrocurzerenone (1) and 16 sesquiterpenoids | — | NMR, HRESIMS | [256] |
| Sesquiterpene structures | Laurencia genus algae | FT-IR, 1H-NMR, 13C-NMR, 1H-1H-COSY, HSQC, HMBC, NOESY | [255] |
| Absolute configuration of tsarvanin A (new sesquiterpenoid) | A. sieversiana | SC-XRD | [114] |
| Polycyclic sesquiterpenoids (biotransformed by M. plumbeus) | — | X-ray crystal structures (hydroxylation stereochemistry) | [268] |
| Biotransformed sesquiterpenoids (from (-)-ambrox, dehydrocostuslactone, α-santonin) | — | High-resolution NMR, X-Ray crystallography, chemical reactions | [267] |
| Eudesma-5,7-diene, eudesma-4,11-diene, α-selinene, eudesm-6-en-4β-ol, guai-6-en-10β-ol, eudesma-5,7-dien-2α-ol, 5α,6α,7α,8α-diepoxy-eudesmane | G. guidonia leaves | 13C/1H NMR data comparison with literature | [12] |
| 5α,6α-epoxy-eudesm-7-ene, 5α,6α-epoxy-eudesm-7-en-9-ol | — | LREIMS, 13C NMR, DEPT 135°, COSY, 1H NMR double resonance | [12] |
| Triterpenoid configurations (new chiral centers) | — | 2D-NMR (ROESY NOE contacts), molecular modeling | [350] |
| Absolute configuration of tricholimbrin E | — | X-ray crystallography | [275] |
| Lanost-24-en-20-ol-3-tetradecanoate (1) | — | IR, 1H NMR, 13C NMR, 1H–1H COSY, HMQC, HMBC, HREI-MS, NOESY | [272] |
| Euphorbol-7-one (2) | — | EIMS, NMR, IR, NOESY | [272] |
| 30-nor-hopan-3b-ol-22-one (3) | — | EIMS, 1H-/13C-NMR, IR, HMBC, NOESY | [272] |
| Hydroxymikaperiplocolide A (1) and B (2) (germacren sesquiterpenoids) | — | HR-ESI-MS, 13C NMR, DEPT, 1H-1H COSY, HMBC, NOESY | [258] |
| Furanoeremophilane sesquiterpenoid (1) | — | HRFABMS, UV, IR, 1H NMR, HMBC, ROESY, Mosher ester methodology | [259] |
| Coptosapterpene A (15) (guaiane-type sesquiterpene) | — | HRESIMS, IR, UV, 1H NMR, 13C NMR, HMQC, 1H–1H COSY, HMBC | [113] |
| Lucidenic acid N (1) and ganoderic acid C2 (4) (triterpenoids) | — | Direct-detected 13C NMR (signal differentiation) | [352] |
| Schipropins A–J (10 new lanostane/cycloartane-type triterpenoids) | — | Extensive spectroscopy, SC-XRD (absolute configurations) | [126] |
| Lupeol, oleanolic acid, ursolic acid, taraxerol | — | 1H-/13C-NMR data comparison with literature | [279] |
| Ursolic acid | — | 1H NMR (methyl doublets, tertiary methyl groups, olefinic/oxymethine protons), 13C NMR (literature match) | [277] |
| Terpenoid structure elucidation program | — | Database of chemical shifts/multiplicities for 161 macronodes | [353] |
| Diverniciaoid A/B, verniciasin C/D (novel terpenoids) | — | Experimental/calculated ECD, HR-ESI-MS, 1D/2D NMR (COSY, HSQC, HMBC, NOESY), CASE algorithms | [354] |
| Selina-4(15),7(11)-diene and germacrene B | Streptomyces pristinaespiralis (SdSWT enzyme) | Catalysis from (2E,6E)-FDP | [244] |
| Cinnamoid A (unprecedented cadinane-derived skeleton) | — | HREI-MS, IR, 1H/13C NMR, COSY, HMBC, ROESY | [7] |
| 4S,5R,7S-8-oxoeremophila-9,11(13)-dien-12-al and 4S,5R,7R-8-oxoeremophila-9,11(13)-dien-12-al (eremophilane-type) | — | HRMS, IR, 1H/13C NMR, COSY, HMBC, NOESY, CD | [257] |
| Myrrhain A (2,3-di-tert-butylbenzofuran-5-ol structure) | Commiphora myrrha | — | [355] |
| 2a,4a-dihydroxy-7aH,8aH,10aH-guaia-1(5),11(13)-dien-8b,12-olide (guaianolide) | Pulicaria crispa | — | [280] |
| Dammarane-type (1–3, acetoxy/carbonyl groups) and norursane-type (4, 24-norursane skeleton) triterpenoids | — | HRESIMS, 1H/13C NMR, HMBC | [8] |
| Oleanolic acid | Olive-oil-production wastes | 1H/13C NMR, COSY, HMBC, HMQC | [132] |
| 11α-hydroxy-3,7-dioxo-5α-lanosta-8,24(E)-dien-26-oic acid and 11β-hydroxy-3,7-dioxo-5α-lanosta-8,24(E)-dien-26-oic acid | G. lucidum | HREIMS, UV, 1H/13C NMR, HMBC, ROESY | [123] |
| 3β,28-dihydroxy-urs-12-ene and nor-ursane derivatives | — | HRESIMS, 1H/13C NMR, COSY, HMBC, NOESY, ECD | [124] |
| Tricholimbrin A (lactone-containing lanostane) | — | HRESIMS, IR, 1H/13C NMR, DEPT, HSQC, HMBC, ROESY, ECD calculations | [275] |
| Ganoderic acids C2, C6, G, B, A, E, and 7β,12β-dihydroxy-3,11,15,23-tetraoxo-lanost-8-en-26-oic acid | G. lucidum | UV, IR, MS, NMR (literature comparison) | [288] |
| Zygophyloside K and G (triterpenoid saponins) | Zygophyllum species | — | [286] |
| 17 triterpenoids/derivatives (limonin, 16-oxoalisol A) | — | LC-MS | [356] |
| Lupeol, lupenone, 28-norolean-17-en-3-one, squalene | S. terebinthifolia | — | [121] |
| Masticadienoic acid, schinol (acid triterpenes, some glycosides) | S. terebinthifolia | — | [121] |
| Betulin, betulinic acid, lupeol, dehydrated/dealkylated terpene hydrocarbons | Birch bark extractives | — | [325] |
| Iridoid glycosides (monoterpene derivatives), crocin (diterpenoid pigment) | HLJDD | MS (fragmentation: glucose loss, H2O loss, RDA) | [348] |
| Selin-7(11)-en-4-ol | Bacterial culture | GC (quantification: 9.8 ± 1.2 mg/L) | [244] |
| 69 compounds (including terpenoids) | ERBECP | GC–MS | [357] |
| Terpenoids | ERBECP | Preliminary phytochemical analysis (quantification: 1.4783 ± 0.0006 mg/100 g) | [357] |
| (E)-cyperusphenol A, mesocyperusphenol A (sesquiterpenoids) | — | Q-TOF–MS (with standards) | [134] |
| Triterpenoid molecular formulas | — | HRESIMS | [124][275] |
| Total triterpenoid content | G. oerstedii (9-day culture) | — (quantification: 686±21 µg/ml) | [292] |
| 24 compounds (including terpenoids) | E. cannabinum | GC–MS | [358] |
| Triterpenoid fragmentation pathways | G. lucidum | HPLC-DAD–ESI-MSn (neutral losses: H2O, CO2; ring cleavages) | [288] |
| Methyl antcinate B, dehydroeburicoic acid | Antrodia cinnamomea | HPLC (calibration curves) | [103] |
| Arjunolic acid, cyclocaric acid B, oleanolic acid | C. paliurus extracts | HPLC (X-Bridge C18 column, UV 205 nm; total content varies by location) | [290] |
| Polar/non-polar/semi-polar terpenoids | — | ESI (polar) and APPI (non-polar/semi-polar) mass spectrometry | [325] |
| Terpenoid fragmentation rules | CWD | — | [359] |
Comparative Distribution and Compositional Variations of Sesquiterpenoids and Triterpenoids
Structural Classification and Compositional Variations of Sesquiterpenoids in Plant Extracts and Essential Oils
Sesquiterpenoids are a structurally diverse class of terpenoids (15-carbon, three isoprene units) widely distributed in plant essential oils, extracts, and fungal sources, with compositional variations driven by species, plant part, geographic origin, extraction method, and temporal factors [107]. They often co-occur with monoterpenoids and triterpenoids (30-carbon, six isoprene units) but exhibit distinct distribution patterns across taxa and tissues [107]. Below is a consolidated overview of sesquiterpenoid composition and variation across sources:
Sesquiterpenoid Composition and Variation Across Plant and Fungal Sources
| Source | Key Sesquiterpenoid Details | Reference |
|---|---|---|
| Peppermint (Mentha piperita) essential oil | ~9% sesquiterpenoids; main component β-caryophyllene | [360] |
| Pigeon pea (Cajanus cajan) leaf essential oil (SFME) | 72.89% sesquiterpenes; major components: α-humulene (17.43 ± 0.40%), α-himachalene (12.97 ± 0.31%), α-bisabolene (12.64 ± 0.34%) | [55] |
| Pigeon pea (Cajanus cajan) leaf essential oil (HD) | 65.26% sesquiterpenes; major components: α-humulene (13.39 ± 0.43%), α-himachalene (13.28 ± 0.36%), α-bisabolene (8.24 ± 0.24%) | [55] |
| Lavender (Lavandula spp.) VOCs (HS–SPME–GC–MS) | 16 sesquiterpenes (majority of sesquiterpenoid components); no sesquiterpene esters, aldehydes, or ketones detected | [361] |
| T. speciosa aerial parts oil | 64.7% of terpenoid fraction; dominated by acyclic-farnesane (26.2%), caryophyllane (11.6%), eudesmane (14.5%) subclasses | [13] |
| T. speciosa root oil | Eudesmanes (isoalantolactone, 95%) as primary class | [13] |
| C. langsdorffii essential oil | Site-specific variations in sesquiterpenes (α-copaene, cubenol, bicyclogermacrene) across seasons | [362] |
| Unspecified essential oil | 78.26% sesquiterpenes; key components β-caryophyllene oxide (33.97%), modephene (23.34%) | [83] |
| Liverwort species | Major compounds: sesquiterpenoids (cuparenes, chamigranes, thujopsanes) and bisbibenzyls; sesquiterpenoids as chemical markers across Japan, China, Poland, Germany, India | [363] |
| Basil essential oil (SFME/HD) | Sesquiterpenes present alongside monoterpenes and phenylpropanoid derivatives (monoterpenes main components) | [364] |
| Lantana camara leaf essential oil | Sesquiterpenoids: germacrene D (6.9%), (E)-β-caryophyllene (40.8%), α-humulene (21.2%), bicyclogermacrene (7.9%), β-elemene (3.5%), spathulenol (0.2–1.5%), (E)-nerolidol, τ-cadinol (0.0–1.0%) | [262] |
| Cyperus rotundus rhizome essential oil (EOCR) | Top 12 key compounds include sesquiterpenoids (caryophyllene oxide, α-cyperone, β-selinene, aristolone, α-copaene, isolongifolen-5-one) | [134] |
| Eucalyptus maidenii outer bark | Main lipophilic sesquiterpenes: aromadendrene, alloaromadendrene, globulol (detected at rt 15.08–24.56 min) | [30] |
| Trichoderma viride mycelia volatiles | 34.07% sesquiterpenes (most abundant terpenoid class); major components caryophyllene oxide, α-bisabolol | [264] |
| Cannabis fan leaves | β-caryophyllene (6.71–45.25%); total sesquiterpenoids > monoterpenoids in Chemovar I/II, comparable in Chemovar III | [327] |
| Egyptian Salsola squamatum (coastal) | 69.77% sesquiterpenes; 61.55% oxygenated sesquiterpenes; major compounds: humulene epoxide, (-)-spathulenol, (-)-caryophyllene oxide, germacrene D, α-humulene (59.72% collectively) | [365] |
| Egyptian Salsola squamatum (inland) | 88.68% sesquiterpenes; 47.39% sesquiterpene hydrocarbons; major compounds: β-pinene, germacrene D, α-humulene, α-muurolene, humulene epoxide, (-)-caryophyllene oxide, β-cadinene (63.70% collectively) | [365] |
| Heracleum lehmannianum essential oil | Key sesquiterpenoids: δ-cadinene (6.2%), α-cadinol (5.7%), τ-muurolol (3.1%), α-muurolene (2.6%) | [366] |
| Uzbek Prangos umbellifera oil | Key sesquiterpenoids: t-cadinol (4.1%), α-humulene oxide (4.0%), caryophyllene oxide (3.6%) | [366] |
| Uzbek Prangos salviifolia oil | Key sesquiterpenoids: α-cadinol (5.7%), 6-epi-shyobunol (5.2%), δ-cadinene (4.4%) | [366] |
| Hop group 1 (North American-derived) | Higher sesquiterpenoids: α-humulene, β-caryophyllene, calarene, α-cubebene, α-copaene, germacrene D, γ-cadinene, farnesol, β-farnesene | [367] |
| Hop group 2 (European-derived) | Higher sesquiterpenoids: α- and β-selinene, trans-α-bergamotene, humulene epoxide II | [367] |
| Artemisia californica (source populations) | Variable sesquiterpene composition; α-bisabolol and unknown terpene F drive pairwise dissimilarity | [80] |
| Pummelo CH variety | Higher acyclic sesquiterpenoids ((E,E)-farnesol, (E)-nerolidol) and cadinyl-type (δ-cadinene) | [2] |
| Pummelo FC variety | Higher germacrene-type (germacrene B, D) and humulene-type (caryophyllene) sesquiterpenoids | [2] |
| Larix cajanderi VOC emissions | 1–3% of total VOCs; increases end of summer; June/July dominated by farnesene/alloaromadrendrene (over half) and β-caryophyllene (17–29%); additional components: α-humulene, aromadendrene, longicyclene, iso-longifolene | [56] |
| Larix cajanderi emission potential | 0.02–0.03 µg g⁻¹ dw h⁻¹ (tree A), 0.04–0.4 µg g⁻¹ dw h⁻¹ (tree B) (lower than L. sibirica: 0.4–1.5 µg g⁻¹ dw h⁻¹) | [56] |
| A. gigantea flowers (female stage) | Emits β-caryophyllene | [368] |
| A. gigantea flowers (male stage) | Emits (Z,E)-α-farnesene, (E,E)-α-farnesene, and oxygenated derivatives | [368] |
| Olive oil (maturation) | Sesquiterpene hydrocarbons: initial slight decrease then increase (α-copaene 43.3% at highest maturity); oxygenated sesquiterpenes: constant then decline | [108] |
| G. mastoporum | Isolated sesquiterpenes: ganomastenol, ganomastenol B, ganomastenol C, ganomastenol D | [106] |
| NAFLD-treating potential | Curcumol (guaiacane sesquiterpene), β-patchoulene, β-caryophyllene | [107] |
Geographic origin significantly influences sesquiterpenoid profiles, as seen in coastal vs. inland Egyptian Salsola squamatum and hop cultivars [351, 399]. Species-specific variations are evident across Heracleum and Prangos species, while source populations of Artemisia californica and pummelo varieties show distinct sesquiterpenoid signatures [8, 477, 573]. Temporal variations include increased sesquiterpene emissions in Larix cajanderi at summer’s end, stage-specific emissions in A. gigantea flowers, and maturation-dependent changes in olive oil sesquiterpenes [387, 462, 522].
Beyond essential oils, sesquiterpenoids are isolated from plant extracts (e.g., methanol, ethyl acetate) and detected via techniques like GC-FID, GC-MS, UPLC-Q-TOF/MS, and UHPLC-UV-MS [126, 270, 274, 413, 879]. Extraction method affects recovery: supercritical CO₂ (sCO₂) has high affinity for sesquiterpenes, while ethanol extraction yields lower concentrations [369]. Biosynthetic diversity is modulated by sesquiterpene synthases; for example, mutations in Shiraz grapes produce α-guaiene, oxidized to the peppery aroma compound rotundone [399, 503]. Sesquiterpenoids also serve as chemotaxonomic markers, such as in C. wenyujin (169 isolated sesquiterpenoids) and liverwort species [414, 585].
Comparative distribution with triterpenoids reveals distinct patterns: in E. dendroides latex, triterpenes dominate (79.53%) over sesquiterpenes (3.75%) [33]; in cannabis, sesquiterpenoids are more abundant in fan leaves, while triterpenoids (β-amyrin, epifriedelanol, friedelin) concentrate in roots and stem barks [327]; in galls, triterpenoids are dominant, with sesquiterpenoids scarce and limited to intact leaves [97]. Fungal sources like G. mastoporum yield sesquiterpenes, while G. lucidum produces abundant lanostane-type triterpenoids (e.g., ganoderic acids) [106].
Triterpenoids (30-carbon, over 126 skeletons) have NAFLD-treating potential (e.g., ginsenosides, ursolic acid) and are present in plant extracts (e.g., neem, Calendula suffruticosa) and fungal sources [979, 1011, 1088]. Structurally distinct from sesquiterpenoids, triterpenoids include cycloartane, betulinic acid, and dammarane series compounds, with distribution varying by plant part (e.g., Uapaca root/trunk barks) and growth conditions (e.g., polyhouse vs. open-field Shankhapushpi) [797, 947, 1093]. Both classes are detected in diverse taxa, including Meliaceae, Dipterocarpaceae, and Tetrastigma [795, 797, 1140].
Structural Profiling and Accumulation Dynamics of Triterpenoids in Plant Tissues and Cuticular Waxes
Terpenoids, including triterpenoids, are specialized metabolites with species-, tissue-, and developmental stage-specific distribution and accumulation. For example, latex contains diverse terpenoids that contribute to its antibacterial, antifungal, anthelmintic, cytotoxic, and insect-repellent activities [370]. Cuticular waxes exhibit distinct terpenoid compartmentalization and dynamic changes across plant species and tissues, as detailed below.
Triterpenoid Content and Distribution in Plant Cuticular Waxes
| Plant/Tissue | Triterpenoid Details | Key Observations | Citation |
|---|---|---|---|
| Wild-type (WT)/mutant (MT) fruit wax | Epicuticular: trace fridelan-3-one; intracuticular: fridelan-3-one, β-amyrin, lupeylacetate, squalene, geranylgeraniol | Intracuticular terpenoids accumulate 120–180 DAF, peak at 180 DAF (MT: 52%, WT: 36%), decline at 210 DAF; fridelan-3-one dominates 150–210 DAF | [371] |
| 'Bingtang' fruit wax (harvest) | Intracuticular: 8 terpenoids (fridelan-3-one, β-amyrin, lup-20(29)-en-3-one, urs-12-en-24-oic acid, farnesol, squalene, campesterol, stigmasterol) | Terpenoids concentrated in internal intracuticular wax; 6 terpenoids detected in intracuticular wax | [263] |
| 'Bingtang' fruit wax (25°C storage) | Total terpenoids peak at 2.94 μg cm⁻² (20 days), decline to 1.32 μg cm⁻² (40 days); farnesol/squalene follow same trend | Terpenoids become most abundant component (39% at 40 days); epicuticular fridelan-3-one/squalene increase with storage | [263] |
| 'Bingtang' fruit wax (4°C storage) | Total terpenoids increase from 2.28 to 3.63 μg cm⁻² (40 days) due to 4.3-fold squalene rise | Terpenoid levels lower than 25°C storage | [263] |
| Eucalyptus outer bark (hydrolyzed lipophilic extracts) | E. urograndis/E. grandis: betulinic, ursolic, oleanolic acids; β-sitosterol; E. maidenii: monoterpenes/sesquiterpenes + triterpenoids | Ursolic acid most abundant (1.9–3.6 g/kg); E. maidenii has betulonic acid (0.6 g/kg) and α-amyrin (0.2 g/kg) | [30] |
| Eucalyptus inner bark | E. urograndis/E. grandis: 0.8 g/kg (ursolic, betulinic acids: 0.2 g/kg each); E. maidenii: 0.5 g/kg (α-amyrin: 0.4 g/kg) | Lower triterpenoid content than outer bark | [30] |
| Lingonberry fruit wax | Pentacyclic triterpenoids (ursane-, oleanane-, lupane-, fernane-, friedelane-, swertane-, taraxerane-type: e.g., α/β-amyrins, lupeol, friedelin) | Diverse triterpenoid skeleton profile | [31] |
| Bilberry fruit wax | α/β-amyrins, their ketones, lupeol, taraxasterol, D:C-friedours-7-en-3-ol | Simpler profile than lingonberry | [31] |
| Strawberry tree fruit wax | Ursane/oleanane-type (α/β-amyrins, uvaol, ursolic/oleanolic aldehydes), lupane-type (lupeol, betulin), taraxasterol, moretenol, hopenone, oleandione | Broad triterpenoid class representation | [31] |
| Bamboo leaf wax | Tocopherol isomers, triterpenols (glutinol, α/β-amyrin, isomultiflorenol, epifriedelanol, lupeol), triterpenyl palmitates | Triterpenols compartmentalized (intracuticular: glutinol, α/β-amyrin; epicuticular: isomultiflorenol, epifriedelanol; even: lupeol); triterpenyl palmitates dominate esterified C16 acid | [372] |
| Apple cuticular wax | Dominated by ursolic/oleanolic acids; minor acids: 'Redkroft' (betulinic), 'Ligol' (pomolic), 'Golden Delicious' (betulinic, hydroxylated oleane/ursane) | Fruits: higher early-season levels, significant esterified forms later (esterified oleanolic acid > free); leaves: same acids, 10x lower levels, higher esterification, stable total content | [332] |
| Pear peel | 101.1–669.1 mg oleanolic acid equivalent/100 g DW; oleanolic acid (164.3–3066.6 μg/g DW) > ursolic acid (125.6–791.2 μg/g DW); peel levels 4–16x higher than flesh | Yaguang: highest oleanolic acid; Yaguang/Guifei: high ursolic acid | [333] |
| Bilberry fruits/leaves | Dominant triterpenoids: oleanolic acid, ursolic acid, α/β-amyrin | Consistent triterpenoid profile across tissues | [333] |
| Tomato fruit wax (development) | 3 triterpenoid alcohols (α/β/δ-amyrin); levels peak at orange (Or) stage; total wax coverage increases IG (6.9 ± 4.6 μg cm⁻²) to Or (18.5 ± 3.3 μg cm⁻²) | Most significant increase IG to mature green (MG) stage | [373] |
| Fruit wax (polar fraction) | Triterpenoids: 33.6% of total wax (pentacyclic triterpene alcohol/ketone: 32.2%); β-amyrin: 14.2% of total wax | Triterpenoids more abundant than fatty acids (27.8%) | [96] |
| Rhizophora mangle leaves | α-amyrin (0.24–6.90 mg g⁻¹ AFDW), β-amyrin (0.47–13.7 mg g⁻¹ AFDW), taraxerol (1.82–6.80 mg g⁻¹ AFDW), oleanolic acid (undetected–4.05 mg g⁻¹ AFDW) | Higher concentrations in brown/black leaves than yellow; taraxerol/β-amyrin primary | [276] |
| Neem tissues | Kernel: C-seco triterpenoids (azadirachtin, salannin); pericarps: ring-intact triterpenoids (azadirone, gedunin); seed kernel/stem/bark: C-seco dominant; pericarp/flower/leaf: ring-intact dominant | AiSQS gene (triterpene biosynthesis) 5x higher in fruit than leaves, 10x higher than flowers | [102] |
| Berry cuticular wax (9 species) | 32% ('Chippewa') to 62% ('Blue Gold') of total wax; 11 triterpenoids; ursolic acid universal; cranberry: 6.63 g 100 g⁻¹ ursolic acid; 'Polaris' blueberry: 9.30 g 100 g⁻¹ ursolic acid, 11.07 g 100 g⁻¹ α-amyrin, 10.2 g 100 g⁻¹ lupeol | Ericaceae: α/β-amyrin, lupeol dominant; Rosaceae: ursolic acid, β-sitosterol, low α-amyrin; lanosterol in 3 species | [374] |
| Grape berry | β-amyrine, lupeol, 6,10,14-trimethyl pentadecan-2-one present in all samples; G. oerstedii (9 days culture): 686±21 µg/ml total triterpenoids | Triterpenoid levels commensurable with sesquiterpenoids; FTIR confirms triterpenoid functional groups | [375], [292] |
| Cyclocarya paliurus leaves | 6 triterpenoids (arjunolic acid, cyclocaric acid B, pterocaryosides A/B, oleanolic acid); total content: 8.15 mg/g (Wufeng ethanol) to 0.05 mg/g (Anji aqueous) | Geographical variation; ethanol extracts contain triterpenoids, aqueous lack pterocaryosides B/A and hederagenin | [290] |
| Olive leaves | Total triterpenoids: absent in April, peak 27.4 mg/g (August), 18.8 mg/g (November); major: ursolic/oleanolic acid, minor: maslinic acid | Highest in fresh August leaves; varies by drying temperature | [294] |
Beyond cuticular waxes, triterpenoids are synthesized in plant calluses, with content differences between lines: CR callus contains 0.18 mg/g DW betulinic acid, 0.08 mg/g DW oleanolic acid, and 0.26 mg/g DW ursolic acid, differing from CYG callus—variations linked to differential expression of triterpenoid biosynthesis genes (e.g., FPS, SS, SE, β-AS) [376]. Phytochemical screening confirms triterpenes in diverse extracts, including forage legumes, Phyllanthus amarus, and bark/leaf/seed tissues [299][377][378][379][92].
Other plant sources include Pteridaceae farinose waxes (triterpenes + flavonoids) [380], Sesbania grandiflora root extract (significant terpenoids) [381], seaweed C. indica (major triterpenes) and C. merica (triterpenes after tannins/saponins) [382], L. camara leaf extracts (terpenoids) [383], and an extract with 24 triterpenoids (coumaroyl ursolic/oleanolic acids, acetylated triterpenoids, caffeoeyltriterpenic acids) identified via UPLC-MS-MS/MS [384]. Coleus forskohlii leaf/stem/root extracts contain triterpenoids, with betulin as a major component in ethanol root extracts [295].
Comparative Distribution of Sesquiterpenoids and Triterpenoids Across Plant Species, Organs, and Developmental Stages
The distribution of sesquiterpenoids and triterpenoids varies across plant species, organs, developmental stages, and geographical locations, with sesquiterpenoids often detected in essential oils and triterpenoids serving as major secondary metabolites in diverse taxa. Below is a consolidated summary of species-specific terpenoid profiles, including key compounds and their relative abundances or concentrations:
Species-Specific Terpenoid Profiles (Sesquiterpenoids and Triterpenoids)
| Organism/Taxon | Sesquiterpenoids (Key Compounds, Concentrations) | Triterpenoids (Key Compounds, Concentrations) | Citations |
|---|---|---|---|
| Haplophyllum lehmannianum | δ-cadinene (6.2%), α-cadinol (5.7%), τ-muurolol (3.1%), α-muurolene (2.6%); fruit/leaf oils: α-humulene, bicyclogermacrene, germacrene D, spathulenol | — | [366] |
| Peucedanum umbellifera (Uzbekistan) | t-cadinol (4.1%), α-humulene oxide (4.0%), caryophyllene oxide (3.6%) | — | [366] |
| Peucedanum salviifolia (Kazakhstan) | δ-cadinene (9.2%), α-cadinol (11.3%), caryophyllene (8.2%) | — | [366] |
| Peucedanum salviifolia (Uzbekistan) | 6-epi-shyobunol (5.2%), δ-cadinene (4.4%), α-cadinol (5.7%) | — | [366] |
| Lavandula stoechas | α-cadinol (4.2%) | — | [385] |
| Liverworts | Cuparenes, chamigranes, thujopsanes (potential chemical markers) | — | [363] |
| Meliaceae family | Present alongside triterpenoids (Guarea cedrata yields diverse sesquiterpenoids) | Limonoids, dammarane, lupane, oleanane, squalane classes; Ekebergia species contain squalane triterpenoids | [24] |
| Dipterocarpaceae (Dipterocarpus, Shorea) | Small sesquiterpenic fraction | Dammarane, oleanane, ursane series; genus-specific biomarkers (e.g., betulonal in Dipterocarpus) | [386] |
| Lamiaceae (Stachys) | — | Ursolic/oleanolic acids (section Olisia), saponin derivatives (stachyssaponins), phytoecdysteroids | [387] |
| Uvariodendron anisatum | — | Present in root extracts | [91] |
| Natural/cultivated plant samples | — | β-sitosterol (high in cultivated samples), stigmasterol (exclusive to cultivated samples); roots/stems richer in terpenoid-steroids | [388] |
| Plantaginis Semen | — | Sumaresinol, oleanolic acid, ursonic acid, oleanolic acid acetate (4 identified) | [95] |
| Azadirachta indica (Neem) | — | Seed kernels: C-seco triterpenoids (azadirachtin, salannin, nimbin, nimbinene); pericarps/stems/bark/flowers/leaves: ring-intact triterpenoids (azadirone, azadiradione, epoxyazadiradione, gedunin) | [102] |
| Euphorbia dendroides (latex) | β-cedrene (most abundant; 3.75% of identified compounds) | Cycloartenol, cycloeucalenol, O-acetyl-delta24 cycloartenol, cycloartenol acetate (79.53% of identified compounds) | [33] |
| Licorice | Biosynthesis pathways enriched in certain comparisons | Glycyrrhizic acid (key component) | [270] |
| Ganoderma lucidum | — | Over 40 ganoderic acids; total triterpenoid content 10x higher than G. sinense | [106] |
| Ganoderma mastoporum | Ganomastenol, ganomastenol B/C/D | — | [106] |
| Seaweeds (C. indica) | — | Among most abundant constituents | [382] |
| Seaweeds (C. merica) | — | Present (after tannins and saponins) | [382] |
| Rose species (R. damascena) | — | Lupeol (1.2%), β-amyrin (0.5%) | [340] |
| Rose species (R. gallica) | — | Lupeol (0.7%), β-amyrin (0.9%); total triterpenoids 2.7% | [340] |
| Rose species (R. alba) | — | Total triterpenoids 0.4% | [340] |
| Cyclocarya paliurus (leaves) | — | Arjunolic acid, cyclocaric acid B, pterocaryoside B/A, oleanolic acid (6 identified); total content varies geographically (highest: 8.15 mg/g, Wufeng ethanol extract; lowest: 0.05 mg/g, Anji aqueous extract) | [290] |
| Olive leaves | — | Oleanolic acid, ursolic acid, maslinic acid; seasonal variation (absent in April, highest: 18.8–27.4 mg/g in November/August) | [294] |
| Centaurea suffruticosa subsp. algarbiensis | (+)-β-guaiene, γ-selinene, isochiapin B (dominant; 0.08–1.73 mg/g DM) | HETU, HMTU, OBTU (43.0–66.9% of total terpenoids; 0.11–4.37 mg/g DM; dominate terpenoid profile) | [389] |
| Elaeagnus rhamnoides/oldhamii | — | Coumaroyl derivatives of ursolic/oleanolic acids, acetylated triterpenoids, caffeoyltriterpenic acids | [384] |
| Ficus hispida | Abundant | 15 triterpenoids (ursolic acid, oleanolic acid derivatives, α-amyrin, lupeol) | [54] |
| Bryophytes (mosses) | 72 isolated/detected | 9 isolated/detected | [86] |
| Bryophytes (hornworts) | — | Present | [86] |
| R. mangle (leaves) | — | Taraxerol, β-amyrin, stigmast-5-en-3β-ol, α-amyrin (higher in brown/black leaves than yellow) | [276] |
| Citrus fruits (flavedo) | — | 5.2–7.6% of total area (hexanic extracts) | [65] |
| Citrus fruits (albedo) | — | 0.8–2% of total area (extracts) | [65] |
Beyond species-specific profiles, terpenoid distribution is shaped by organ specificity, developmental stage, and environmental factors. Organ-specific accumulation includes secretory trichomes, fruit mesocarp, and stem cortex [390]; for example, Pinus radiata needles/bark contain sesquiterpenoids (unknown sesquiterpenoid alcohol and trans-farnesol, respectively) but roots do not [391], while Helianthus annuus leaves have twice as many sesquiterpenoids as monoterpenoids, and petals show the opposite pattern [392]. Cultivar differences are evident in grape species (Vitis vinifera hybrids have linalool as the most abundant terpenoid, while V. amurensis ‘Shanputao’ has none [393]) and Alstroemeria (terpenoids dominate VOC profiles, with cultivar-specific discriminants like citronellyl acetate [394]).
Developmental stage variation affects terpenoid composition: flower buds to fully open flowers retain sesquiterpene hydrocarbons as the most abundant volatile class (62.2–77.9%) [62]; young hop plants have higher sesquiterpenoid levels than monoterpenes [395]; and moss gametophytes emit fewer terpenoid VOCs than mature sporophytes [396]. Neem pericarp/kernel triterpenoid levels vary across developmental stages [102], and olive leaf triterpenoids are absent in April but peak in November/August [294].
Environmental and population factors also influence terpenoid distribution: total sesquiterpenoids decrease 81% from southern to northern populations [397]; Pinus heldreichii/P. nigra sesquiterpenes better reflect inter-population diversity than monoterpenes [398]; and C. paliurus triterpenoid content varies geographically [290]. Domestication has increased volatile sesquiterpenoid abundance in cultivated H. annuus compared to wild populations [392].
Terpenoids are also present in non-plant or processed materials: Cannabis Fructus [399], propolis extracts [400], and traditional formulations like Pingwei Powder [401]. Overall, sesquiterpenoids and triterpenoids exhibit species-, organ-, developmental-, and latitudinal-specific patterns, highlighting their diverse roles in plant chemistry.
Terpenoid Composition Variations in Food Matrices, Fossil Resins, and Environmental Samples
Terpenoids are a diverse class of phytochemicals, comprising one of the largest classes of natural compounds with wide industrial applications, including flavors, fragrances, and medicines [402]. Their distribution and composition vary significantly across food matrices, fossil resins, and environmental/biological samples, with key variations tied to source, processing, and environmental factors.
Terpenoid Profiles and Variations Across Food Matrices
| Food Matrix | Terpenoid Characteristics | Citations |
|---|---|---|
| Fortified wines | Campari: 83% of total VOMs (limonene dominant); Marsala: <2% of total VOMs | [403] |
| Vermouth varieties | VermouthR/VermouthD: limonene/menthol dominant; VermouthW: estragole, α-terpinyl acetate, anethol dominant | [403] |
| Spent coffee grounds (Brazil, Colombia, Ethiopia, Guatemala) | 2.46–4.11% of volatile fingerprint; carvacrol, limonene, 2-menthene dominant | [402] |
| Mango/citrus peels | Monoterpene/sesquiterpene hydrocarbons; d-limonene dominant in citrus peel | [404] |
| Apricot fruits | 77 species (17.95% of total volatiles); total content 51.93 ± 16.45 µg/g (27.23–96.03 µg/g across cultivars) | [405] |
| Apricot juices | Among most abundant volatiles (with benzaldehyde, esters, norisoprenoids) | [406] |
| Peach volatiles | Mainly esters, alcohols, terpenoids; enzyme treatments alter levels (extraction reduces linalool/R-terpineol/menthol; clarification increases limonene/β-ionone) | [406] |
| Pear fruits/juices | Terpenoids: limonene, citronellal, (E,E)-R-farnesene; clarification enzyme reduces levels | [406] |
| Grignolino grape berries | Geraniol, p-ment-1-ene-7,8-diol, geranic acid dominant; vintage/location influence levels (PCA links to optimal temperature days) | [343] |
| Cannabis samples | Terpenoid number/concentration increase with CTHC (1.0–1.9% CTHC: ≤3 terpenoids; 12.2% CTHC: 25 terpenoids) | [407] |
| Malaysian stingless bee propolis | 14.3% terpenoids; T. binghami extract highest (2.19 mg/mL) | [408] |
| Ginger/myrcia/zanthoxylum piperitum | Monoterpenes/terpenoids; zanthoxylum piperitum emits 24–42× more monoterpenes than others | [409] |
| Unspecified samples | Terpenoid content: LW = RLW > SSW | [410] |
| Phytoncides essence | D-limonene (18.7%), α-terpineol (15.2%), α-pinene (7.3%) | [411] |
| Black tea (JBT vs FBT) | JBT: 21–23% of total aroma (trans-linalool oxide, terpinolene, linalool; OAV >1 for linalool); FBT: 15–16% of total aroma | [412] |
| Pequi plants | 11 terpenoids (77 total volatiles); β-cis-ocimene/dendrolasin as discrimination markers | [43] |
| Cannonau grapes (skins/juice) | Skins: 28.6 µg kg⁻¹ (NS), 31.1 µg kg⁻¹ (CS); juice: 25.07 µg kg⁻¹ (NS), 35.9 µg kg⁻¹ (CS); sun exposure influences monoterpenes; α-terpineol absent in wine (fermentation biotransformation) | [413] |
| Fermented KJ | Up-regulated terpenoids (β-sinensal, perilla alcohol, geranyl acetate); concentrations differ between LBKJ/PBKJ | [414] |
| Kombucha black tea | Loses terpenoids after 21 days of fermentation | [415] |
| Mango cultivars | 814: 961.96 μg/kg (79.16% of volatiles, caryophyllene/α-caryophyllene/α-selinene dominant); TA: 11.66 μg/kg (0.88%); Lvsong/Shengshi/Baodaohuang: no sesquiterpenes | [416] |
| Sorghum grains | 10 sesquiterpenoids; accumulation differs between white/colored grains | [417] |
| Mushrooms (storage-dependent) | Fresh (Day 1): high diterpenoids/monoterpenoids; longer storage: increased triterpenoids/sesquiterpenoids; 3-hydroxysintaxanthin/armillaric acid abundant early; diterpenoids/terpene glycosides peak late | [418] |
| Torronte´s grape distillates | Rich in sesquiterpenoids (β-cadinene, δ-selinene, R-humulene, aromandrene, nerolidol) and diterpene manoyl oxide; sesquiterpenes distinguish via PCA | [419] |
| G. pfeifferi | Farnesylhydroquinones and triterpenoids (applanoxidic acids A/C/G, ganoderal A, ganoderol A/B) | [420] |
| TTP70 | 65.34 ± 1.06% w/w triterpenes (maslinic acid, oleanolic acid, ursolic acid, uvaol, erythrodiol) | [421] |
| Yellow Cuban propolis (YCP) | Type A: 6.8–21.4 μg/100 μg extract (cycloartenol, lupeol, β-amyrin dominant); Type B: 2.4–12.8 μg/100 μg extract (higher acetylated derivatives) | [34] |
| Milk | Plant-derived terpenoids transferred (some degraded/modified by rumen bacteria); variability linked to pasture diversity, altitude, season, management | [326] |
In fossil resins, sesquiterpenoid distribution varies by age: extant dammar resin is dominated by germacrene D, α-copaene, and β-caryophyllene, while Miocene and Eocene resins show cadalene-based sesquiterpenoids (calamenene, dihydro-ar-curcumene, cadalene) [422]. Triterpenoids in extant, Miocene, and Eocene resins are generally similar, with β-amyrin as the most abundant, alongside β-amyrone, α-amyrone, and α-amyrin [422]. Resin from high-yield trees has higher limonene content and a lower α/β-pinene ratio (1.13) compared to low-yield trees (1.57), with additional sesquiterpenoids (trans-α-bergamotene, humulene, caryophyllene oxide) detected only in low-yield tree resin [423]. Fossil resin extract TIC is mainly dominated by sesquiterpenoids (more abundant than triterpenoids) including 2,6-dimethyl-1,2,3,4-tetrahydronaphthalene, cadinene, and calamelene (highest abundance), while major triterpenoids are A-neo-ursa-3(5),12-diene and oleana-2,12-diene [424]. Dammar resins (fossil and fresh) have a small sesquiterpenic fraction and a major triterpenic fraction (C30) from dammarane, oleanane, and ursane series [386]. Fresh Dipterocarpus resins have a genus-specific triterpenic biomarker (betulonal) absent in Shorea resins [386], while ancient dammar resin samples contain dammaradienone and oleanane/ursane derivatives [386].
In environmental and biological samples, propolis from F. longipes contains both mono- and sesquiterpenes, while A. mellifera propolis contains only sesquiterpenes, with 26 volatiles exclusive to F. longipes and 8 to A. mellifera [425]. Uninfected R. brevipes sporocarps have a diverse terpenoid profile absent in infected sporocarps [89]. Maiganga paleoflora shows higher diterpenoid abundance than triterpenoids and sesquiterpenoids, indicating gymnosperm dominance [426]. Lignite samples contain saturated and monounsaturated C15 sesquiterpenes of cadinane and drimane types, with aromatic sesquiterpenoids dominated by cadalene [427]. Hopanoids are important non-aromatic cyclic triterpenoids in lignites, with αβ-C31 hopane (22R) and hop-17(21)-ene as predominant [427]. Non-hopanoid triterpenoids in lignites include oleanane, ursane, and lupane types (e.g., des-A-oleanenes, olean-12-ene) and their aromatic derivatives (e.g., 24,25-dinoroleana-1,3,5(10),12-tetraene), which are biomarkers for angiosperms [427]. Jinsuo Basin lignites show distinct sesquiterpenoid and triterpenoid distributions: pale lignites have higher saturated diterpenoids (av. 126.0 μg/g TOC) indicating gymnosperm dominance, while dark lignites have higher saturated triterpenoids (av. 35.9 μg/g TOC) and aromatic triterpenoids (av. 526.8 μg/g TOC) indicating angiosperm dominance [428]. Hopanoids in Jinsuo lignites are more abundant in pale (av. 771.2 μg/g TOC) than dark (av. 446.0 μg/g TOC) samples, with C31 17α(H),21β(H)-homohopane(22R) as most abundant [428]. Bog samples have alicyclic hydrocarbons dominated by triterpenes, with taraxerene and neohop-13(18)-ene dominant in Bolshoe and Bakchar bogs, and diploptene in Central bog [104]. Diterpenoid concentrations in some samples are low compared to angiosperm-derived triterpenoids [429]. Organic matter under spruce has several-fold higher sesquiterpene concentrations than under birch, with triterpene concentrations lower in birch than spruce or mixed treatments [430]. Sesquiterpenes in these samples include bornylacetate, junipene, and cadidene (no dominant compound), while β-sitosterol is the most abundant triterpene [430]. Isoprene lipids in some samples include triterpenes (28.4%), sesquiterpenes (18.2%), and diterpenes (18.2%) as top components [173]. UMS contains sesquiterpenoids (e.g., absindiol, cichorioside M), monoterpenoids, diterpenoids, and triterpenoids, marking the first report of terpenoids in this matrix [347]. Host lignite aliphatic fraction has sesquiterpenoids (e.g., longifolene 12, cadinene) and triterpenoids (e.g., des-A-lupane), with triterpenoids more prominent than sesquiterpenes [424]. Biomarker assemblages in some environmental samples include sesquiterpenoids, diterpenoids, and triterpenoids (including oxidation/degradation products) [431].
Impact of Biotic and Abiotic Factors on Sesquiterpenoid and Triterpenoid Production and Emission Patterns
Sesquiterpenoids and triterpenoids exhibit distinct distribution patterns across plant tissues and species, with compositional variations driven by both biotic and abiotic factors. Their abundance, composition, and emission profiles vary widely by plant species, tissue type, and environmental conditions, as summarized in the table below.
Sesquiterpenoid and Triterpenoid Distribution, Composition, and Emission Across Plant Species and Tissues
| Plant Species/Tissue | Key Sesquiterpenoids (SQTs) | Key Triterpenoids (TTs) | Key Findings | Citations |
|---|---|---|---|---|
| Cannabis sativa (hemp) | β-caryophyllene, α-humulene, β-farnesene, γ-eudesmol (8 molecules total) | More abundant in benzyladenine (BA)-treated extracts | SQTs = 9% of identified compounds; GA₃ treatment increased SQT abundance | [432][60][344][241] |
| Pinus armandi saplings | α-copaene, α-cubebene, α-humulene, α-muurolene, β-caryophyllene, δ-cadinene, germacrene, germacrene D-4-ol, longifolene | — | Concentrations vary by tissue type/treatment; L. qinlingensis inoculation increases total SQTs over time | [433] |
| Aquilaria species (agarwood) | SQTs linked to G. candidum inoculation (detected in BR/Out groups) | — | SQT production induced by fungal injection | [434] |
| Scots pine | longifolene, α-muurolene | — | SQTs decrease over incubation; ventilation accelerates decline | [435] |
| Artemisia californica leaves | 17 SQTs (α-bisabolol, unknown terpene F primary for population dissimilarity) | — | Source populations differ in SQT concentration/composition; precipitation treatments alter profiles | [80] |
| Helianthus annuus leaves | Twice as many SQT compounds as monoterpenoids (MTs) | — | SQT/MT production weakly correlated (R² = 0.39) | [392] |
| 278 plant study | 21 SQTs (bicyclosesquiphellandrene, β-caryophyllene, γ-muurolene, α-amorphene consistent) | — | 4 chemotype classes; class 1 = 36% bicyclosesquiphellandrene, class 3 = 31% longiverbenone, classes 2/4 = calarene (25%), germacrene D (13%), γ-cadinene (10%) | [436] |
| Betula pubescens (downy birch) | SQTs, oxygenated SQTs (OSQTs) | — | Total SQT emissions 5× (2017) and 4× (2019) higher than MTs; 2019 OSQT emissions 5.8× higher than MTs | [437] |
| Baizongia/Geoica galls, intact leaves | Scarce, primarily in intact leaves | Most abundant terpenoid class; Baizongia galls > Geoica galls > intact leaves | TTs dominate; SQTs scarce in galls | [97] |
| Olive leaves | — | Oleanolic acid, ursolic acid, maslinic acid | Seasonal variation: absent in April, highest in August (27.4 mg/g) and November (18.8 mg/g) | [294] |
| Angiosperm epicuticular waxes/gums | — | α- and β-amyrin (dominant); oleana-2,12-diene, ursana-2,12-diene, lupa-2,22-diene, α/β-amyrone | TTs are natural product precursors/derivatives | [438] |
| Licorice (Glycyrrhiza spp.) | — | Glycyrrhizin, glycyrrhetinic acid | Salt stress impacts accumulation: severe/low-salt > middle-salt; low-salt > control; bAS expression higher in salt-stressed groups | [439] |
| Shankhapushpi | — | Ursolic acid equivalent (UAE) | Polyhouse-grown plants have higher TT content (up to 11.1 ± 0.4 mg UAE/g) than open-field (1.7 ± 0.1 mg UAE/g) | [330] |
Biotic factors, particularly herbivory, significantly impact sesquiterpenoid production and emission. Herbivore damage (e.g., by S. frugiperda, D. saccharalis, L. qinlingensis, or weevils) increases sesquiterpenoid concentrations and emissions, with long-term damage leading to sesquiterpene-dominated blends over green leaf volatiles (GLVs) [440][441]. In P. armandi, L. qinlingensis inoculation elevates specific sesquiterpenes (δ-cadinene, longifolene, germacrene) in phloem/xylem [433], while weevil feeding on conifer seedlings increases stem bark emissions of longifolene/δ-cadinene and induces α-copaene/α-humulene [335]. Insect elicitors (Lh-LP, Ls-LP, Ls-EMP) trigger higher β-caryophyllene and TMTT release than artificial damage [442]. Huanglongbing (HLB) infection in citrus reduces sesquiterpenoids (valencene, β-cadinene, nootkatone) and increases monoterpenoids, suggesting biosynthetic pathway interruption [238].
Abiotic factors—temperature, light, drought, CO₂, soil type, pollution, and ontogeny—also modulate terpenoid profiles. Temperature positively correlates with both sesquiterpenes (P < 0.05) and triterpenes (P < 0.01) [443], and drives emission differences: (E,E)-α-farnesene is only detected in infested Arabidopsis at 27°C [444], while grape berry terpenoids correlate with optimal temperature days [343]. Light intensity linearly increases hemp sesquiterpenoids (β-caryophyllene, α-humulene) [60]. Drought effects vary: hemp early flowering water deficit increases sesquiterpenes [228], grapevine 'Callet' drought boosts sesquiterpenes for sugar transport [445], and hemp drought + nanosilicon alters β-caryophyllene/α-humulene content [344]. Elevated CO₂ reduces sesquiterpenes [446], while cement dust increases oxygenated sesquiterpenes (spathulenol) in polluted sites [447]. Geographic factors (latitude/longitude) affect monoterpenoids but not sesquiterpenoids, though soil type correlates with sesquiterpenoids (R² = 0.03; p = 0.004) [436][80]. Eucalyptus sesquiterpene composition shows strong ontogenetic effects [448], and olive leaf triterpenoids vary with drying temperature [294]. Plant growth regulators (PGRs) target biosynthetic pathways: GA₃ promotes sesquiterpenes via (E,E)-farnesyl diphosphate, while BA stimulates triterpenes via squalene [241].
Functional and Chemical Property Comparisons Between Sesquiterpenoids and Triterpenoids
Structural Classification and Skeletal Diversity of Sesquiterpenoids and Triterpenoids from Plant Sources
Terpenoids—encompassing sesquiterpenoids and triterpenoids—are ubiquitously distributed across plant families including Apiaceae, Clusiaceae, Lamiaceae, Lauraceae, Myristicaceae, Myrtaceae, Rutaceae, and Zingiberaceae, where they contribute to essential oil composition and exhibit diverse bioactivities (antioxidant, antimicrobial, anti-inflammatory, antidiabetic, anticancer, antiallergic) [449]. These compounds are structurally varied: sesquiterpenoids (15-carbon, three isoprene units) include guaiacane, bicyclic, and other skeletons, while triterpenoids (30-carbon, six isoprene units from GGPP) boast over 126 carbon skeletons and 18,000+ compounds, spanning pentacyclic (lupanes, oleananes, ursanes) and tetracyclic (dammarane, tirucallane, lanostane) types [450][107].
Plant sources yield both classes, with some species producing both: Bixa orellana contains sesquiterpenes (major volatile compounds in annatto extracts) and triterpenoids [451]; Lantana camara leaf essential oil features sesquiterpenoids (germacrene D, (E)-β-caryophyllene, α-humulene, bicyclogermacrene) alongside triterpenes/esters (e.g., lantadenes) [262]; Cyperus rotundus rhizomes provide sesquiterpenoids (α-cyperone, β-selinene, nootkatone, valencene) and triterpenoids (β-amyrin, stigmasta-5,22-dien-3-ol) [134][452][453]; Boswellia dracunculifolia organic extracts are triterpenoid-rich, while its essential oils contain sesquiterpenes [98]; Euphorbia dendroides latex has triterpenes (79.53%, cycloartenol, cycloeucalenol) and sesquiterpenes (3.75%, β-cedrene) [33]. A study of 278 plants identified 21 sesquiterpenoids, classifying four chemotypes by dominant compounds: bicyclosesquiphellandrene (36%, class 1), calarene (25%, class 2), longiverbenone (31%, class 3), and germacrene D (13%, class 4) [436].
Comparison of Sesquiterpenoid and Triterpenoid Properties, Bioactivities, and Examples
| Category | Sesquiterpenoids | Triterpenoids |
|---|---|---|
| Chemical Structure | 15-carbon, 3 isoprene units; diverse skeletons (guaiacane, bicyclic) [107] | 30-carbon, 6 isoprene units (from GGPP); 126+ skeletons, 18k+ compounds [450][107] |
| Subtypes/Examples | Curcumol (Curcuma phaeocaulis), β-patchoulene (Pogostemon cablin), β-caryophyllene (Rosmarinus officinalis, Cinnamomum cassia, Ocimum basilicum, Lavandula angustifolia) [107]; sesquiterpene lactones (15, 16) [454]; s-Cadinol, eugenol [449][455]; elemene (Curcuma wenyujin) [456] | Lupeol (Cratoxylum formosum, Citrus hystrix) [449][263]; ganoderic acid derivatives (G. lucidum) [287]; β-amyrin, urs-12-en-24-oic acid, friedelan-3-one [449]; oleanolic acid, ursolic acid, betulinic acid, glycyrrhetinic acid, asiatic acid [457][107][458]; euphane, tirucallane (24, 25) [454][458]; 18--glycyrrhetinic acid (licorice), betulinic acid (Betula etnensis) [456]; arjunglucoside II (Fructus Corni) [457] |
| Physicochemical Traits | High lipophilicity (farnesol, log P = 4.32) [459]; volatile, prone to oxidation/evaporation (β-caryophyllene → caryophyllene oxide; isocaryophyllene, α-bergamotene losses) [336] | Less volatile; present in cuticular waxes (squalene, friedelan-3-one) [263]; triterpenols (glutinol, β-amyrin, α-amyrin) in bamboo intracuticular wax [372]; limited solubility (maslinic acid, oleanolic acid, ursolic acid in TTP70: 83–85 μg/mL) [421] |
| Bioactivities | Antimycobacterial (sesquiterpene lactones 15, 16: MIC 16–128 μg mL⁻¹) [454]; bactericidal (s-Cadinol, eugenol) [449][455]; anti-inflammatory (C. rotundus nootkatone, α-cyperone, valencene, β-selinene) [134]; anticancer (elemene: lung adenocarcinoma therapy) [456]; insecticidal/fungicidal (caryophyllene oxide) [460] | Antimycobacterial (tirucallanes 24, 25: MIC 64, 32 μg mL⁻¹) [454]; anti-inflammatory (lupeol) [455]; anti-inflammatory/cytotoxic (ganoderic acid C1, lanostane) [287]; antidiabetic (euphane-triterpenoids: 11β-HSD1 inhibition) [458]; anticancer (oleanolic acid, ursolic acid: leukemia telomerase inhibition, cervical cancer growth inhibition; 18--glycyrrhetinic acid: ROS/RNS/ferroptosis in TNBC; betulinic acid: HO-1-mediated ferroptosis; Fructus Corni compounds: anti-glioma) [461][457][456]; HMGCR inhibitory (acidic triterpenoids) [289]; insecticidal/fungicidal [460] |
| Extract Content | N/A | CPLa: 6%, CPLe: 3.5%, CAFa/CAFe: undetectable [462] |
Functional and chemical differences between the two classes are notable: sesquiterpenoids’ tight structure enhances efficacy relative to other terpenes, while triterpenoids with more hydrophilic groups are preferred for multi-target antidiabetic effects [450]. Triterpenoids dominate terpenoid natural products (alongside diterpenoids and sesquiterpenoids) and often have complex cyclic scaffolds, with pentacyclic types showing broad bioactivities [463]. Their structural diversity—from cyclic sesquiterpenes to triterpenyl palmitates—supports roles in plant defense, organoleptic properties, and therapeutic applications [436][372][287]. Terpenoids (including both classes) are frequently cited for insecticidal/fungicidal activity: 43 terpenoid compounds have insecticidal effects, 29% of fungicidal compounds are terpenoids, and nine (e.g., caryophyllene oxide, linalool, thymol) exhibit both, relevant for Attini ant management [460].
Comparative Functional Properties of Sesquiterpenoids and Triterpenoids in Antimicrobial, Anticancer, and Metabolic Regulation
Terpenoids exhibit diverse functional properties across antimicrobial, anticancer, and metabolic regulation contexts, with distinct activities observed between sesquiterpenoids and triterpenoids. Their efficacy is driven by chemical structure and physicochemical properties, with terpenoids generally more effective against bacteria and protozoans than terpenes [464].
Antimicrobial Activity of Sesquiterpenoids and Triterpenoids
| Compound Class | Specific Compounds/Extracts | Activity Details | Citations |
|---|---|---|---|
| Sesquiterpenoids | Geraniol, citronellol, farnesol | Geraniol: 98% fungal inhibition at 200 μg/mL (higher than citronellol); farnesol (log P = 4.32) penetrates skin easily | [459] |
| Sesquiterpenoids | Sesquiterpenes 15 and 16 (Asteraceae) | Antimycobacterial activity (MIC: 16–128 μg/mL), comparable to positive control lactone 26; linked to alkylating properties and lipophilicity | [454] |
| Triterpenoids | Friedelin (friedelane triterpene) | Antimicrobial against Gram-positive bacteria; high content in ‘Satsuma’ mandarin intracuticular wax (defense against Penicillium digitatum) | [181, 1098] |
| Triterpenoids | Oleanolic acid | Targets Bacillus subtilis, methicillin-sensitive/resistant Staphylococcus aureus | [465] |
| Triterpenoids | Tirucallane triterpenes 24 and 25 (A. adstringens) | Antimycobacterial activity (MIC: 64 and 32 μg/mL, respectively) | [454] |
| Triterpenoids | Ursolic acid (OA) and oleanolic acid (EA) analogs (Y11, Y13) | Inhibit Ebola virus (EBOV) pseudoparticles (IC50: 50 nM) by targeting viral fusion protein HR2 domain | [466] |
| Triterpenoids | 5% (w/v) chloroform fraction (triterpenoid-rich) | High antimalarial activity against Plasmodium falciparum (IC50: 1.4 μg/mL) | [467] |
| Triterpenoids | B. tetraphylla leaf triterpenoids | Active against bacteria and fungi | [468] |
| Terpenoids (general) | Plant extracts | Antimicrobial activity attributed to triterpenoids | [469] |
Nematode and Viral Modulatory Activity of Terpenoids
| Compound Class | Specific Compounds/Extracts | Activity Details | Citations |
|---|---|---|---|
| Sesquiterpenoids | Rishitin; cotton plant sesquiterpene aldehydes | Rishitin: nematostatic effects on Ditylenchus destructor at 100 µg/ml; aldehydes: complete larval motility loss at 125 µg/ml | [470] |
| Triterpenoids | Azadirachtin; glycinoeclepin A | Azadirachtin: suppresses nematode hatching and has nematocidal activity; glycinoeclepin A: stimulates Heterodera glycines larval hatching at 10–6 µg/ml | [470] |
| Triterpenoids | Triterpenoid-rich fractions (F2) | Anti-proliferative effects (IC50: 1.73 µg/ml, more potent than other fractions) | [471] |
Anticancer Activity of Sesquiterpenoids and Triterpenoids
| Compound Class | Specific Compounds/Extracts | Activity Details | Citations |
|---|---|---|---|
| Triterpenoids | Celastrol (quinone methide triterpene) | Proteasome inhibitor; suppresses human prostate cancer growth in nude mice; induces leukemia cell apoptosis via topoisomerase II inhibition | [465] |
| Triterpenoids | Oleanolic acid | Inhibits Epstein-Barr virus early antigen activation (linked to anti-tumor activity) | [465] |
| Sesquiterpenoid Alkaloids | Triptonine B (Tripterygium hypoglaucum) | Inhibits HIV replication in H9 lymphocytes (EC50 < 0.10 μg/ml, therapeutic index > 1000) | [465] |
| Triterpenoids | Salaspermic acid | Inhibits HIV replication (EC50: 5 μg/ml); activity linked to acetal linkage (ring A) and carboxyl group (ring B) | [465] |
| Sesquiterpenoids | Commiphora opobalsamum isolates | Inhibit hormone-independent prostate cancer cell proliferation (concentration-dependent, normal cell-sparing) | [280] |
| Sesquiterpenoids | Guaianolide (Pulicaria crispa) | Cytotoxic against EJ-138 human bladder carcinoma (IC50: 5.8 ± 0.2 mmol/l) | [280] |
| Sesquiterpenoids | 2α-hydroxy-5α,6α-epoxyalantolactone; axillarin (P. crispa) | Antineoplastic and cytotoxic activity, respectively | [280] |
| Triterpenoids | Ganoderic acid derivatives (Ganoderma lucidum) | Prominent contributors to cytotoxic effects; modulate NF-κB, STAT3, PI3K/AKT/mTOR, and cell cycle/apoptosis pathways | [675, 1105] |
| Sesquiterpenoids | Artemisinin and derivatives | Inhibit cancer cell proliferation, bypass MDR; mechanisms: iron-mediated peroxide cleavage, cell cycle arrest, apoptosis, anti-angiogenesis | [27] |
| Triterpenoids | Celastrol; cucurbitacins; alisol derivatives; pachymic acid | Celastrol: targets multiple signaling pathways; cucurbitacins: inhibit proliferation, arrest cell cycle, target F-actin/STAT3; alisol derivatives: induce ER stress/apoptosis; pachymic acid: induces apoptosis/inhibits invasion | [27] |
| Sesquiterpenes | Elemene (Curcuma wenyujin) | Clinical use for lung adenocarcinoma (combined with conventional therapy); anticancer effects linked to glutathione metabolism (decreased GSH/GSSG, reduced SLC7A11/glutaminase, upregulated GCLM, downregulated GS) | [456] |
| Triterpenoids | 18-glycyrrhetinic acid (licorice) | Induces ROS/RNS, lipid peroxidation, ferroptosis in MDA-MB-231 cells (downregulates SLC7A11, reduces GSH/GPx) | [456] |
| Triterpenoids | Betulinic acid (Betula etnensis) | Induces HO-1-mediated ferroptosis (reduces GSH, enhances ROS/LOOH) | [456] |
| Triterpenoids | Fructus Corni components (oleanolic acid, ursolic acid, arjunglucoside II) | Principal anti-glioma agents | [457] |
| Triterpenoids | Hedyotis diffusa isolates (ursolic acid, oleanolic acid, gypsogenic acid) | Ursolic acid: growth-inhibitory against diverse tumor cell lines; oleanolic acid: inhibits ras-transformed R6 cells (non-toxic to normal fibroblasts); ursolic acid more potent than oleanolic acid | [472] |
| Triterpenoids | Structural classes (cucurbitanes, dammaranes, ergostanes, etc.) | Cytotoxic/antiproliferative against breast cancer cell lines (MCF-7, MDA-MB-231); ursolic acid (Calluna vulgaris) inhibits MCF-7 proliferation (G1 arrest followed by cell death) | [473] |
| Triterpenoids | Ganoderiols, ganodermatriol, ganoderol B/F, lucidumol | Inhibit androgen-independent prostate cancer proliferation; lucidumol A + ganoderic acid-β: anti-HIV activity; ganoderiol F: inhibits topoisomerases I/II, DNA synthesis (G2 arrest in HepG2, Huh7, K562 cells) | [474] |
| Triterpenoids | Ganoderic acid-DM (GA-DM) | Increases Bax, Apaf-1, cytochrome-c, Beclin-1, LC3 (induces autophagy/apoptosis); enhances HLA class II expression (increases immune susceptibility) | [474] |
| Triterpenoids | Ganoderic acid-T (GA-T) | Inhibits topoisomerase-I (interferes with telomerase 1-DNA interaction) | [474] |
| Triterpenoids | Ganoderic acid-C (GA-C) | Competitively inhibits protein prenyltransferase (PPP), blocking farnesyl pyrophosphate biosynthesis | [474] |
Metabolic Regulation by Terpenoids
| Compound Class | Specific Compounds/Extracts | Activity Details | Citations |
|---|---|---|---|
| Terpenoids | Moringa extracts (ethanol/water) | Ethanol extracts yield sesquiterpenoids abundantly; water extracts yield terpenoids | [475] |
| Sesquiterpenoids | Constituents 3, 4, 9 | No DGAT inhibition at 125.0 μg/mL | [476] |
| Triterpenoids | Compounds 2, 7, 8 | Moderate DGAT inhibition (IC50: 31.7, 26.4, 44.3 μM, respectively); C-28 carboxy group critical (compound 1: IC50 >250 μM) | [476] |
| Sesquiterpenoids | FPE sesquiterpenoids | Antioxidant potential (DPPH IC50: 3.25–4.18 μM) | [477] |
| Triterpenoids | Betulinic acid derivatives | Antioxidant activity; synergistic effects with hindered phenols (radical regeneration) | [478] |
| Sesquiterpenes | β-caryophyllene, α-humulene | Contribute to antiseptic, antimicrobial, anti-inflammatory properties in plant extracts | [479] |
| Triterpenes | Lupeol | Bioactive candidate for anti-inflammatory effects | [449] |
| Sesquiterpenes | Costunolide | Stimulates β-islet insulin secretion (inhibits nitric oxide synthase); normo-glycemic/hypolipidemic | [480] |
| Sesquiterpenes | Eremanthin (sesquiterpene lactone) | Stimulates insulin release, increases insulin sensitivity, reduces HbA1c/lipids, increases HDL-cholesterol | [480] |
| Triterpenoids | Medicinal plant triterpenoids; Boswellic acid | Stimulate pancreatic insulin release, ameliorate oxidative stress; Boswellic acid inhibits aldose reductase/AGE formation | [480] |
| Triterpenoids | Ganoderma lucidum triterpenoids; Wolfiporia extensa triterpenes | Ganoderma: inhibit α-glucosidase/PTP1B; Wolfiporia: improve insulin sensitivity | [481] |
| Triterpenoids | Natural triterpenoids | Inhibitors of sterol regulatory element-binding proteins (SREBPs, metabolic disease target) | [482] |
| Triterpenoids | Prostate cancer metabolic targets | Hit different metabolic targets in prostate cancer | [483] |
| Terpenoids | Vitamins | Regulate metabolism, act as antioxidant protectants | [484] |
| Triterpenoids | C. paliurus ethanol extracts (triterpenoid-rich) | Better lipid-lowering effects in STZ-induced diabetic mice; triterpenoids (cyclocaric acid B, oleanolic acid) linked to cholesterol-lowering (cyclocaric acid B: decreases apolipoprotein B48; oleanolic acid: increases HDL-C, decreases atherogenic lipids) | [290] |
| Triterpenoids | Medicinal mushroom triterpenoids | May prevent/treat metabolic syndrome and associated diseases | [485] |
Triterpenoids also modulate immune responses to enhance infection defense [486]. Sesquiterpenes are more efficacious than other terpenes due to their tightly packed structure, while triterpenes with more hydrophilic groups are preferred for multi-target antidiabetic effects [450].
Physicochemical and Biophysical Property Variations Between Sesquiterpenoids and Triterpenoids
Sesquiterpenoids and triterpenoids exhibit distinct physicochemical properties that shape their behavior and functional roles. Key characteristics of sesquiterpenoids include high lipophilicity, volatility, ozone reactivity, and low hygroscopicity of their photooxidation products, while triterpenoids are marked by limited solubility and permeability, self-assembly behavior, and stability under specific metabolic conditions.
Physicochemical Properties of Sesquiterpenoids and Triterpenoids
| Class | Property | Specific Compound/Example | Value/Outcome | Citation(s) |
|---|---|---|---|---|
| Sesquiterpenoids | Lipophilicity (log P) | Farnesol | 4.32 (correlates with enhanced skin permeation) | [459] |
| Volatility | Isocaryophyllene (C₁₅H₂₄, MW 204), β-caryophyllene | Continuous evaporative losses when exposed to air | [336] | |
| Ozone reactivity | Compounds with 2–3 double bonds | Up to 90% loss at 20 ppbv; 100% loss at 100 ppbv | [487] | |
| Ozone reactivity (notable compounds) | β-caryophyllene, α-humulene | Rarely detected in ambient air due to rapid oxidation | [488] | |
| Hygroscopicity of photooxidation SOA (85% RH) | α-humulene, β-caryophyllene | Growth factors (GF) = 1.01–1.04; anti-correlation between GF and precursor MW | [489] | |
| MLR calculation accuracy for enthalpies of vaporization | Sesquiterpenes vs. broader terpenoid classes | Higher accuracy (R² = 0.97, Q² = 0.92) than broader classes | [490] | |
| Triterpenoids | BCS classification | Rosemary extract triterpenoids (ursolic, betulinic acids) | Class II (high permeability, low solubility) or IV (low permeability, low solubility) | [491] |
| Apparent permeability (Papp) | Rosemary extract triterpenoids | Low values even in free formulations | [491] | |
| Solubility (unformulated vs. solid dispersions) | TTP70 triterpenoids (maslinic, oleanolic acids) | ≈18% released after 5 h (unformulated); up to 1 mg/mL solubility and 86% dissolution (1:5 P407 solid dispersions) | [421] | |
| Self-assembly behavior | Oleanolic, ursolic, maslinic acids | Form vesicular self-assemblies in aqueous binary mixtures | [35] | |
| Self-assembly behavior (betulinic acid) | Betulinic acid | Forms gels in 19 out of 22 neat organic liquids | [35] | |
| Solubility enhancement (triterpenic acids) | Triterpenic acids (sodium/potassium salts) | Increased solubility in aqueous mixtures when converted to salts | [35] | |
| Metabolic stability | Triterpenes | Remain unchanged; not detected in metabolized forms | [492] |
Notably, sesquiterpenoids’ high reactivity with ozone and volatility limit their persistence in ambient environments, while triterpenoids’ poor solubility and permeability can be mitigated through formulation strategies like solid dispersions or salt conversion. These contrasting properties underpin their distinct applications and environmental fates.
Computational Analysis of Sesquiterpenoid and Triterpenoid Binding Interactions and Thermodynamic Properties
Computational approaches have been applied to characterize the thermodynamic properties of sesquiterpenoids and terpenoids, with predictive accuracy varying by compound class and method. For mono- and sesquiterpenes, triterpenoids, and sesquiterpenoid high-energy–density fuels (HEDFs), key findings from regression, density functional theory (DFT), and molecular docking studies are summarized below:
Predictive Performance of Computational Methods for Terpenoid and Sesquiterpenoid Thermodynamic Properties
| Compound Class | Method/Model | Property Predicted | Key Metrics | Citations |
|---|---|---|---|---|
| Mono- and sesquiterpenes | Multiple linear regression (MLR) | Enthalpy of vaporization | R² = 0.97; Q² = 0.92 | [490] |
| Terpenoids | MLR | Enthalpy of vaporization | R² = 0.69; Q² = 0.46; average deviation ≈ 1 kcal mol⁻¹ | [490] |
| Sesquiterpenoid HEDFs | DFT (screened/optimized + triple correction) | Enthalpy of combustion (ΔcH) | Average absolute error = 2.6% (295 compounds) | [493] |
| Sesquiterpenoid HEDFs | MLR-based QSPR (4 QC features) | ΔcH | R² (training) = 0.957; R² (test) = 0.956; RMSE (training) = 8.626 kcal/mol; RMSE (test) = 9.012 kcal/mol | [493] |
| Triterpenoids (beta-sitosterol) | Molecular docking | Binding to target genes | Targets: PGR, NCOA2, PTGS1; higher incorporation into PGR, NCOA2, NR3C2 | [494] |
| Triterpenoid-related (+)-catechin | Molecular docking | Binding to HCC-related proteins | LibDock scores: 71.1138 (ESR1); 115.911 (CAT) | [494] |
The lower accuracy for terpenoids (compared to mono- and sesquiterpenes) is attributed to the implicit SMD solvation model’s lack of hydrogen-bond considerations [490]. For sesquiterpenoid HEDFs, integrating DFT with quantitative structure–property relationship (QSPR) modeling—using extreme gradient boosting (XGBoost) and Shapley additive explanation (SHAP) to identify key quantum chemical (QC) descriptors—effectively guides ΔcH design for novel compounds [493]. Molecular docking studies on triterpenoids from A. chinensis Planch root (a triterpenoid-rich source of active ingredients) highlight their binding interactions with human target genes and hepatocellular carcinoma (HCC)-related proteins, indicating good binding ability [494].
Biosynthetic Pathway Origins and Accumulation Patterns of Sesquiterpenoids and Triterpenoids in Plants
Sesquiterpenoids and triterpenoids—two major terpenoid classes—exhibit distinct biosynthetic origins: both are synthesized via the mevalonate pathway, while other terpenoids (e.g., monoterpenes, diterpenes) derive from the methylerythritol phosphate (MEP) pathway [155]. This divergence shapes their accumulation patterns across plant tissues, in response to environmental cues, and under experimental manipulations, as summarized below. Functionally, sesquiterpenoids often support plant defense, while triterpenoids display diverse bioactivities including antitumor, antibacterial, and antiviral effects [495]. Geographically, sesquiterpenoid compositions in tansy plants showed no significant correlation with latitude or longitude (unlike monoterpenoids), though both classes had low but significant association with soil type [436]. For extraction, ethanol efficiently recovered sesquiterpenoids and triterpenoids in relative abundance from Moringa and bitter leaf, while water extracted the highest terpenoid concentrations from Moringa [475]. In fruit volatile profiles, sesquiterpenes like farnesenes were major components in pear juice [406], contributing to flavor and aroma, while triterpenoids support structural and defensive functions in cuticular waxes [263][372].
Accumulation Patterns of Sesquiterpenoids and Triterpenoids Across Plant Systems
| Terpenoid Class | Plant System | Key Observations | Citations |
|---|---|---|---|
| Sesquiterpenoids | Tansy plants | Consistent presence of bicyclosesquiphellandrene, β-caryophyllene, γ-muurolene, and α-amorphene; total concentrations 1.3–25.5 pmol g⁻¹ leaf fresh weight; Class 4 had significantly lower concentrations than other classes | [436] |
| Sesquiterpenoids | Weevil-damaged seedling stem bark | Total emissions increased from 29.4 ± 19.6 to 208.0 ± 71.9 ng g(DW)⁻¹ h⁻¹; longifolene and δ-cadinene emissions enhanced | [335] |
| Triterpenoids | Bamboo leaves | Glutinol, β-amyrin, and α-amyrin accumulated in intracuticular wax (young/old leaves); isomultiflorenol and epifriedelanol in epicuticular wax (old leaves only) | [372] |
| Triterpenoids | 'Bingtang' fruits | Fridelan-3-one, β-amyrin, and squalene detected in intracuticular wax; total terpenoid content (triterpenoid-dominated) peaked at 2.94 μg cm⁻² after 20 days storage at 25°C before decreasing | [263] |
| Triterpenoids/Sesquiterpenoids | Grafted plants | 59 of 109 differentially accumulated terpenoids were triterpenoids (highest proportion), followed by 37 sesquiterpenoids; most elevated post-grafting | [191] |
| Triterpenoids | BSHC vs. BCYC plant samples | 2α-hydroxyursolic acid showed 63,354.94-fold higher abundance in BSHC | [496] |
Sesquiterpenoids also contribute to antiseptic, anti-microbial, and anti-inflammatory properties in P. peruviana calyx extracts [479], further underscoring their functional diversity alongside triterpenoids.
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