Terpenoids: Higher Advanced article Timothy P Devarenne, Texas A&M University, College Station, Texas, USA Article Contents . Introduction Based in part on the previous version of this Encyclopedia of Life Sciences . Nomenclature and Biosynthesis of the Isoprenoid Unit (ELS) article, Terpenoids: Higher by W David Nes and Wenxu Zhou. Diterpenes . Triterpenes . Tetraterpenoids Online posting date: 15th September 2009 Terpenoids (or isoprenoids/isopentenoids) are a diverse by humans for many purposes such as flavourings in food, group of compounds that are found throughout nature scents in perfume and drugs to fight diseases such as can- and are biosynthesized through the successive condensa- cer. This article examines the synthesis, distribution and tion of the five-carbon compound isoprene. Higher function of higher terpenoids as well as the regulation of the genes responsible for the production of these molecules. terpenoids are complex structures that possess minimal- ly between 20 and 40 carbon atoms. Although higher terpenoids are found in all organisms, plants produce the largest array of higher terpenoids in terms of number, Nomenclature and Biosynthesis of the structure and function. These plant-derived higher terpe- noids can be utilized by humans for purposes such as drugs Isoprenoid Unit to fight diseases or as feedstocks for biofuel production. Terpenes and terpenoids constitute a very large family of The genes responsible for producing these plant of higher natural products. Approximately 20 000 different terpenes terpenoids are just now beginning to be identified and and terpenoids have been identified, embracing a bewilder- these studies are showing that higher terpenoids are ing but fascinating array of skeletal types that contribute essential for plant growth, development and defence to the many varied functions of these molecules in nature. against pathogens. The term terpene was originally used to describe C10H18 hydrocarbons occurring in turpentine oil, a complex mixture of terpenes. The term terpenoid has, over the years, acquired a generic significance and is used almost interchangeably with isoprenoids (oid, meaning like) and isopentenoids, with no universal agreement on terminol- Introduction ogy in this area. An isoprenoid unit (or isoprene unit) is a five-carbon-atom structure with the isopentane carbon Living organisms, whether they are plants, animals or skeleton of isoprene, a product of the dry distillation microbes, are composed of similar compounds, derived (pyrolysis) of natural rubber. A terpene unit is considered from a few basic biochemical pathways operating in to comprise 10 carbon atoms, from which all designations cells, including the terpenoid pathway. The unity of life, originate: hemi (C ), mono (C ), di (C ), sester (C ), tri apparent from the uniformity in structural constitution of 5 10 20 25 (C ), tetra (C ) and poly (4C )(Table 1). biomolecules, indicates that phenotypic change and genetic 30 40 40 In the biological unit, the branched end of isoprene is evolution are coordinately regulated with the function known as the tail and the other end is known as the head played by natural products during ontogenetic and (Figure 1). During biosynthesis of terpenoids, the tail of the phylogenetic maturation. Terpenoids are lipids that have isoprene intermediates is bound to a diphosphate group (or played a central role in growth and development of living pyrophosphate; Figure 1). The terms prenyl, for example a systems. Additionally, plant-derived terpenoids are used prenyl alcohol, and polyisoprenoid are both in common use to refer to linear (open-chain) isoprenoids. An example of a prenol is phytol, the C20 diterpene side-chain of chlorophyll. ELS subject area: Plant Science Some authors have used terpene to refer only to hydro- carbons based on an integral number of C5 units as shown in How to cite: Table 1, and ‘isoprene’ (or more properly, isoprenoid) to Devarenne, Timothy P (September 2009) Terpenoids: Higher. In: designate the whole class of natural products derivable from Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. a(C)n structure. Terpenes have also been defined as DOI: 10.1002/9780470015902.a0001916.pub2 5 compounds whose carbon skeleton can be dissected into ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 1 Terpenoids: Higher Table 1 Classification of terpenes and terpenoids Classification No. of carbon atoms No. of isoprene units Example Diterpenes 20 4 Gibberellic acid (Figure 2) Sesterterpenes 25 5 Ophiobolin Triterpenes 30 6 b-Amyrin (Figure 3) Sterols 27–30 6 Stigmasterol (Figure 3) Tetraterpenes 40 8 b-Carotene (Figure 2) Polyterpenes 440 48 Rubber (Figure 2) isoprenoid units joined in a regular linkage (e.g. head-to- thus higher terpenoids and carbon from IPP to be tail), or in an irregular linkage (e.g. head-to-head). incorporated into amino acids. The basic C5 isoprene unit for terpenoid biosynthesis can originate from three different pathways: (1) the mevalonate (MVA) pathway, (2) the nonmevalonate pathway or Diterpenes methylerythritol phosphate (MEP) pathway and (3) the mevalonic acid shunt. The MVA pathway occurs in the Diterpenes are C20 compounds formed from C20 GGPP cytosol of animals and plants, whereas the MEP pathway mainly produced by plants. Plant diterpenes are used for occurs in bacteria and the plastids of plants. It appears that defence against pathogens and herbivoures, for hormone green algae only contain the MEP pathway localized in the production, and by humans as drugs. For example, the plastid. In plants, monoterpenes, diterpenes, carotenoids, diterpene taxol, produced by the Pacific yew tree, Taxus ubiquinones and phytol are produced in the plastid via the brevifolia, is well known as an anticancer agent. GGPP MEP pathway. All other plant terpenoids (sesquiterpenes, itself can be covalently attached, posttranslationally, to triterpenes and polyterpenes) are produced using the MVA proteins and act as a membrane anchor. This is common pathway (Rohmer, 2003). See also: Terpenoids: Lower for nontransmembrane proteins involved in membrane- The MVA pathway utilizes three molecules of C2 acetyl– associated signalling such as Rab guanosine triphospha- CoA to form C6 HMG (3-hydroxy-3-methylglutarate)– tase (GTPase) proteins. See also: Membrane Targeting: CoA, which is reduced to C6 MVA. MVA is then phos- Methods; Proteins: Postsynthetic Modification – Function phorylated twice to produce MVA diphosphate (MVAPP), and Physical Analysis; Taxol which undergoes decarboxylation to give rise to the Conifer trees secrete a resin in response to insects that C5 biological isoprene unit isopentenyl diphosphate create a hole in the tree. The resin is made up of equal (IPP). IPP is then isomerized to dimethylallyl diphosphate amounts of monoterpenes and diterpenes and small (DMAPP; Figure 1). amounts of sesquiterpenes that can bury the invading In the MEP pathway, IPP is produced by the condensa- insect. The diterpenes in the resin act to seal the hole as well tion of glyceraldehyde-3-phosphate and pyruvate to form as have a role in defence (Keeling and Bohlmann, 2006). 1-deoxyxylulose-5-phosphate, which is reduced and iso- Although the resin in conifers is constitutively present in merized to MEP for which the pathway is named. MEP resin ducts, wounding or herbivory has been shown to form then undergoes a series of reactions, the last of which traumatic resin ducts as well as induce the expression of produces both IPP and its isomer DMAPP (Figure 1; diterpene synthesis genes, which is mediated by the wound- Rohdich et al., 2002). induced production of the signalling compound methyl In both the MVA and MEP pathways, IPP is combined jasmonate. Typical diterpenes in resin include abietic and with DMAPP in a head-to-tail condensation to form C10 isopimaric acids. Castor bean also produces the diterpene, geranyl diphosphate (GPP). Successive head-to-tail addi- casbene, that function as an antifungal agent. tions of IPP can then produce terpenoid intermediates such Gibberellins (GAs; Figure 2) are diterpene plant hor- as C15 farnesyl diphosphate (FPP) and C20 geranylgeranyl mones that were initially isolated from the fungus diphosphate (GGPP) that are used to form diterpenoids, Gibberella fujikuroi and were subsequently found to be triterpenoids and tetraterpenoids, respectively. Coupling widespread among higher plants. GAs are produced by the reactions that can lead to the biosynthesis of acyclic 30 cyclization of GGPP into the kaurene skeleton, which is carbon atom molecules, triterpenes (e.g. coupling of FPP, then further metabolized to over 50 different GAs with a to give squalene), and of acyclic 40 carbon molecules, C20 ent-gibberellane or C19 ent-20-nor gibberellane skele- tetraterpenes (e.g. coupling of GGPP to give phytoene), ton. GAs regulate many growth aspects of plants including involve head-to-head condensations. Cyclization and shoot elongation, fruit set and the de novo synthesis of oxidation reactions follow coupling reactions to give the a-amylase. G. fujikuroi is a pathogen of rice and takes desired end product. See also: Cholesterol, Steroid and advantage of the growth-stimulating properties of GAs by Isoprenoid Biosynthesis secreting GAs into the rice host causing unnatural growth, The MVA shunt is a bidirectional pathway that allows which results in infertile flowers and plant death. See also: carbon from amino acids to be incorporated into IPP and Plant Growth Factors and Receptors 2 ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net Terpenoids: Higher tail head head head OPP OPP tail tail (a) Isopentenyl diphosphate (IPP) Farenesyl diphosphate (FPP) MVA pathway MEP pathway 3 Acetyl-CoA O OH + OP O OH O O OH HMG-CoA Pyruvate Glyceraldehyde-3- HO S-CoA phosphate O OH OH MVA HO OH OP O OH 1-Deoxyxylulose-5-phosphate OPP OPP OH (b) IPP DMAPP OP OH OH Methylerythritol-4-phosphate OPP OH Hydroxymethyl butenyl-PP OPP OPP (c) IPP DMAPP Figure 1 Head and tail positions of the basic isoprene unit and pathways for producing IPP. (a) Head and tail position for IPP and FPP.