Medically Useful Plant Terpenoids: Biosynthesis, Occurrence, and Mechanism of Action
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molecules Review Medically Useful Plant Terpenoids: Biosynthesis, Occurrence, and Mechanism of Action Matthew E. Bergman 1 , Benjamin Davis 1 and Michael A. Phillips 1,2,* 1 Department of Cellular and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; [email protected] (M.E.B.); [email protected] (B.D.) 2 Department of Biology, University of Toronto–Mississauga, Mississauga, ON L5L 1C6, Canada * Correspondence: [email protected]; Tel.: +1-905-569-4848 Academic Editors: Ewa Swiezewska, Liliana Surmacz and Bernhard Loll Received: 3 October 2019; Accepted: 30 October 2019; Published: 1 November 2019 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: isoprenoids; plant natural products; terpenoid biosynthesis; medicinal plants; terpene synthases; cytochrome P450s 1. Plant Terpenoids Terpenoids, or isoprenoids, are isoprene-based natural products with fundamental roles in the metabolism of all organisms [1]. Terpenoid chemical diversity is especially high in plants where many can be considered secondary metabolites. Such non-essential, specialized plant terpenoids underlie many ecological interactions between plants and animals [2,3], acting as allelochemicals to attract pollinators, repel herbivores, or attract herbivore predators [4]. The evolution of terpenoid secondary metabolism in plants began with the recruitment of genes from primary metabolism [5] and accelerated due to the proliferation of cytochrome P450 and terpene synthase gene families in the genomes of plants [6,7]. Terpenoid chemical diversity partly reflects a natural history marked by herbivory stress and other selective pressures imposed by animals, resulting in a broad array of functionalized terpenoids in the plant kingdom pre-selected for their potent biological activities towards animals [8]. This selective process may have been facilitated by the general similarity of protein folds and motifs between plant and animal proteins, resulting in plant secondary metabolites with natural affinity for animal proteins by virtue of having been produced by plant enzymes composed of the same amino acids [9]. Thus, pre-selection and emergence of plant secondary metabolites with biological activity towards animals may have both an evolutionary and a biochemical basis. As a consequence, many plant terpenoids have found fortuitous uses in medicine, and the terpenoid family of natural products has been a valuable source of medical discoveries [10–12]. Hundreds more allegedly possess medicinal properties, but the testing process is painstaking and Molecules 2019, 24, 3961; doi:10.3390/molecules24213961 www.mdpi.com/journal/molecules Molecules 2019, 24, x FOR PEER REVIEW 2 of 22 Molecules 2019, 24, 3961 2 of 23 Hundreds more allegedly possess medicinal properties, but the testing process is painstaking and resource intensive.intensive. The The true true number number of plantof plant terpenoids terpenoids in nature in nature which couldwhich potentially could potentially be screened be 5 forscreened therapeutic for therapeutic applications applications is unknown is butunknown is likely but>10 is5, likely including >10 >, 12,000including from >12,000 the diterpenoid from the groupditerpenoid alone group [13]. Whilealone this[13]. number While this is small number compared is small to moderncompared combinatorial to modern combinatorial methods, the leadmethod compounds, the lead discovery compound rate discovery may be rate significantly may be significantly higher for plant higher natural for plant products natural due products to the aforementioneddue to the aforementioned pre-selection pre effects.-selection But owing effects. to theirBut owing high degree to their of chemicalhigh degree functionalization of chemical andfunctionalization metabolic specialization, and metabolic many specialization, are produced inmany small are amounts, produced only in in responsesmall amounts, to elicitation, only orin accumulateresponse to exclusivelyelicitation, inor specialized accumulate tissues, exclusively necessitating in specialized microbial tissues, production necessitating or major microbial advances byproduction plant breeding or major and advances genetic improvementby plant breeding to obtain and sugeneticfficient improvement quantities to to investigate obtain sufficient clinical potentialquantities [14 to, 15investigate]. This in turnclinical necessitates potential a [14,15 detailed]. This understanding in turn necessitates of the biosynthetic a detailed enzymes, understanding genes, andof the regulatory biosynthetic programs enzymes, of a genes, given candidateand regulatory compound. programs Here of we a given review candidate the current compound. understanding Here ofwe the review biosynthesis, the current occurrence, understanding and mechanismof the biosynthesis, of action occurrence, of a select and group mechanism of plant terpenoidsof action of of a medicalselect group significance. of plant terpenoids Due to the largeof medical number sign ofificance. plant terpenoids Due to the described large number in the literatureof plant terpenoids in various healthdescribed contexts, in the weliterature have excluded in various those health of acontexts, purely nutritional, we have excluded nutraceutical, those of or a anti-oxidant purely nutritional, nature andnutraceutical, instead focused or anti on-oxidant compounds nature with and specific instead pharmacological focused on activity. compounds Cardenolides with suchspecific as + + digoxin,pharmacologic whichal inhibit activity. cardiac Cardenolides Na+/K+ ATPase such as anddigoxin, improve which cardiac inhibit muscle cardiac contraction Na /K ATPase and stroke and volume,improve havecardiac been muscle reviewed contraction recently and [16,17 stroke] and thereforevolume, have were been not covered reviewed here. recently [16,17] and therefore were not covered here. 2. Terpenoid Precursor Pathways 2. Terpenoid Precursor Pathways The carbon backbone of highly functionalized terpenoid natural products is formed through the condensationThe carbon backbone of the central of highly metabolic functionalized intermediates terpenoid of terpenoid natural products metabolism, is formed isopentenyl through and the dimethylallylcondensation diphosphateof the central (IDP metabolic and DMADP) intermediates (Figures1 andof 2terpenoid). Two distinct metabolism, biochemical isopentenyl pathways and in naturedimethylallyl synthesize diphosphate them: the (IDP 2C-methyl- and DMADPd-erythritol-4-phosphate) (Figures 1 and 2). Two (MEP) dist pathwayinct biochemical and the mevalonic pathways acidin nature (MVA) synthesize pathway [18 them:–20]. Thethe cytosolic 2C-methyl MVA-D- pathwayerythritol supplies-4-phosphate IDP and (MEP) DMADP pathway in essentially and the all eukaryotesmevalonic acid and (MVA) the archaea, pathway whereas [18– the20]. MEPThe cytosolic pathway MVA is functional pathway in supplies eubacteria IDP and and in theDMADP plastids in ofessentially algae, higher all eukaryotes plants, and and protists the archaea, [21]; photosynthetic whereas the MEP organisms pathway utilize is functional both precursor in eubacteria pathways and butin the separate plastids them of intoalgae, di ffhighererent subcellularplants, and compartments. protists [21]; photosynthetic In plants, there organisms is limited utilize evidence both of exchangeprecursor ofpathways IDP/DMADP but separate pools between them into the different plastid and subcellular cytosol, usually compartments. in the context In plants, of secondary there is metabolismlimited evidence [22–26 of]. exchange In general, of the IDP/DMADP MEP pathway pools supplies between C5 prenyl the plastid diphosphates and cytosol, for the usually synthesis in the of 5 Ccontext10 monoterpenes, of secondary C20 diterpenes,metabolism and [22 C–4026tetraterpenes]. In general, while the theMEP MVA pathway pathway supplies provides C the prenyl same 10 20 40 universaldiphosphates precursors for the forsynthesis the synthesis of C monoterpenes, of C15 sesquiterpenes, C diterpenes, C27–29 sterols, and C C 30tetraterpenestriterpenes, while and their the saponinMVA pathway derivatives. provides the same universal precursors for the synthesis of C15 sesquiterpenes, C27–29 sterols, C30 triterpenes, and their saponin derivatives. Figure 1.1.Biosynthesis Biosynthesis of isopentenylof isopentenyl (IDP) (IDP and) dimethylallyland dimethylallyl diphosphate diphosphate (DMADP) (DMADP via the mevalonic)