Medically Useful Plant Terpenoids: Biosynthesis, Occurrence, and Mechanism of Action

Abstract

Specialized plant terpenoids have found fortuitous uses in medicine due to their evolutionary and biochemical selection for biological activity in animals. However, these highly functionalized natural products are produced through complex biosynthetic pathways for which we have a complete understanding in only a few cases. Here we review some of the most effective and promising plant terpenoids that are currently used in medicine and medical research and provide updates on their biosynthesis, natural occurrence, and mechanism of action in the body. This includes pharmacologically useful plastidic terpenoids such as p-menthane monoterpenoids, cannabinoids, paclitaxel (taxol^®), and ingenol mebutate which are derived from the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway, as well as cytosolic terpenoids such as thapsigargin and artemisinin produced through the mevalonate (MVA) pathway. We further provide a review of the MEP and MVA precursor pathways which supply the carbon skeletons for the downstream transformations yielding these medically significant natural products.

Keywords: cytochrome P450s; isoprenoids; medicinal plants; plant natural products; terpene synthases; terpenoid biosynthesis.

Figure 1

Biosynthesis of isopentenyl (IDP) and dimethylallyl diphosphate (DMADP) via the mevalonic acid (MVA) pathway and alternative MVA pathway (boxed) in the cytosol. Enzyme abbreviations are as follows; AACT—acetoactl-CoA thiolase, HMGS—hydroxymethylglutaryl-CoA synthase, HMGR—hydroxymethylglutaryl-CoA reductase, MVK—mevalonate kinase, PMK—phosphomevalonate kinase, MVD—mevalonate 5-phosphate decarboxylase, IDI—isopentenyl diphosphate isomerase, PMD—phosphomevalonate decarboxylase, IPK–isopentenyl phosphate kinase, NDX—Nudix hydrolase, AcCoA—acetyl-CoA. OP and OPP signify mono- and diphosphate moieties, respectively. P_i represents inorganic phosphate.

Figure 2

Biosynthesis of IDP and DMADP via the MEP pathway in the plastid. Enzyme abbreviations are as follows: DXS—1-deoxy-d-xylulose 5-phosphate synthase, DXR—1-deoxy-d-xylulose 5-phosphate reductoisomerase, MCT—2C-methyl-d-erythritol 4-phosphate cytidyltransferase, CMK—4-(cytidine 5′-diphospho)-2C-methyl-d-erythritol kinase, MDS—2C-methyl-d-erythritol-2,4- cyclodiphosphate synthase, HDS—4-hydroxy-3-methylbut-2-enyl diphosphate synthase, HDR—4-hydroxy-3-methylbut-2-enyl diphosphate reductase. For intermediates, GAP—d-glyceraldehyde- 3-phosphate, DXP—1-deoxy-d-xylulose 5-phosphate, MEP—2C-methyl-d-erythritol 4-phosphate, CDP–cytidyl diphosphate, MEcDP—2C-methyl-d-erythritol-2,4-cyclodiphosphate, HMBDP—1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate, IDP—isopentenyl diphosphate, DMADP—dimethylallyl diphosphate; OP and OPP signify mono- and diphosphate groups, respectively.

Figure 3

Steps in the biosynthesis of (−)-menthol and related p-menthanes in peppermint (M. x piperita). Enzyme abbreviations are as follows; LS–(−)-limonene synthase, L3OH—(−)-limonene 3-hydroxylase, iPD— (−)-trans-isopiperitenol dehydrogenase, iPR—(−)-trans-isopiperitenone reductase, iPI—(+)-cis-isopulegone isomerase, PR—(+)-pulegone reductase, MR—(−)-menthone reductase, MFS—(+)-menthofuran synthase. OPP signifies a pyrophosphate group. The box indicates the branch pathway leading to (+)-menthofuran.

Figure 4

Steps in the biosynthesis of major cannabinoids in C. sativa and C. indica. Metabolites are as follows: GDP—geranyl diphosphate, OA–olivetolic acid, CBGA–cannabigerolic acid, CBDA—cannabidiolic acid, CBD—cannabidiol, THCA—Δ⁹-tetrahydrocannabinic acid, THC—Δ⁹-tetrahydrocannabinol, DVA—divarinic acid, CBGVA—cannabigerovaric acid, CBDVA—cannabidivarinic acid, CBV—cannabivarin, THVA—tetrahydrocannabivarinic acid, THV—tetrahydrocannabivarin. Enzymes are as follows: GOT—geranylpyrophosphate:olivetolate geranyl transferase, THCAS—tetrahydrocannabinolic acid synthase, CBDAS—cannabidiolic acid synthase, THCAS—tetrahydrocannabinolic acid synthase, CBDAS—cannabidiolic acid synthase. The traditional name Δ⁹-THC is used in the text while the monoterpene numbering scheme is used in this figure. OPP indicates a diphosphate group.

Figure 5

Biosynthetic pathway for the formation of cannflavin A and B in C. sativa and C. indica. This terpenophenolic compound is produced from geranyl diphosphate (GDP) or dimethylallyl diphosphate (DMADP) and the flavonoid chrysoeriol derived from naringenin in C. sativa and C. indica. SAM—S-adenosylmethionine, SAhc—S-adensoylhomocysteine. Enzymes are as follows: CHS—chalcone synthase, CHI—chalcone isomerase, FNS—flavone synthase, F3’H—flavanoid 3’ hydroxylase, CsOMT21—O-methyltransferase 21, CsPT3—prenyltransferase 3.

Figure 6

Steps in the biosynthesis of the sesquiterpene lactone artemisinin in A. annua. Enzyme abbreviations are as follows: ADS–amorpha-4,11-diene, CYP71AV1–cytochrome P450 71AV1, DBR2–double bond reductase 2, Aldh1–aldehyde dehydrogenase 1. OPP signifies a diphosphate moiety and FDP represents farnesyl diphosphate. The open arrow indicates photooxidative steps involved in the formation of the endoperoxide ring which remain uncharacterized.

Figure 7

Initial biosynthetic steps for the formation of the sesquiterpene lactone thapsigargin in T. garganica. Enzyme abbreviations are as follows: TgTPS2–epi-kunzeaol synthase, TgCYP76AE2–cytochrome P450 76AE2. OPP signifies a diphosphate moiety. The open arrow indicates uncharacterized steps between epi-dihydrocostunolide and thapsigargin.

Figure 8

Simplified pathway for the biosynthesis of paclitaxel (taxol) in T. brevifolia (pacific yew). GGDP–geranylgeranyl diphosphate, OPP–diphosphate, Bz–benzyl, Ac–acetyl, CoA–Coenzyme A. Enzymes: TS–taxa-4(5),11(12)-diene, T5αOH–taxadiene-5α-hydroxylase, TAT–taxadiene-5α-ol-O-acetyl transferase, T9αDH–taxane-9α-dehydrogenase, DBAT–10-deacetylbaccatin III-10-O-acetyl transferase, BAPT–baccatin III:3-amino,13-phenylpropanoyl transferase, T2’-αOH–taxane-2’α-hydroxylase, DBTNBT–debenzoyltaxol N-benzoyl transferase, PAM–phenylalanine aminomutase, PCL–β-phenylalanyl-CoA ligase. The open arrow represents multiple oxidative steps to arrive at the hypothetical intermediate.

Figure 9

Proposed pathway for the initial steps leading to the Euphobia factor ingenol mebutate in Euphorbia spp., as per [168]. GGDP represents geranylgeranyl diphosphate and OPP signifies a diphosphate group. Enzyme abbreviations: CS-casbene synthase, CYP726A27–cytochrome P450 726A27, CYP71D445–cytochrome P450 71D445, ADH1–alcohol dehydrogenase 1.