Terpenoid mevalonate biosynthetic pathway

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

Terpenoid substances are of broad distribution and diverse function in insects. One set, elaborated by the mandibular glands of Acanthomyops claviger, acts both as a defensive secretion and as an alarm releaser. When fed Cu-labeled acetate or mevalonate, laboratory colonies of these ants produce radioactive citronellal and citral, providing unambiguous evidence for de novo synthesis of these terpenes by the ant. The incorporations of these precursors implicate the mevalonic acid pathway as the likely biosynthetic route. 

The diverse, widespread and exceedingly numerous class of natural products that are derived from a common biosynthetic pathway based on mevalonate as parent, are synonymously named terpenoids, terpenes or isoprenoids, with the important subgroup of steroids, sometimes singled out as a class in its own right. Monoterpenes, sesquiterpenes, diterpenes and triterpenes are ubiquitous in terrestrial organisms and play an essential role in life, as we know it. Although the study of terrestrial terpenes dates back to the last century, marine terpenes were not discovered until 1955. 

This brief survey of natural products derived from the 3-deoxy-D-oro6iTk>-heptulosonic acid 7-phosphate pathway illustrates the economy of fimda-mental biosynthetic pathways. The relative economy and simplicity of the biological degradative and energy-yielding reactions is paralleled in the biosynthetic reactions. For example, 3-deoxy-D-oroW o-heptulosonic acid 7-phosphate is a precursor of a host of aromatic products mevalonic acid is the progenitor of the terpenoids and steroids, and 5-aminolevulinic acid of the porphyrins. 

In D. punctata, JH III is biosynthesized in retrocerebral endocrine organs, the corpora allata (CA) [45]. The sesquiterpenoid skeleton of this compound is formed through the terpenoid biosynthetic pathway from acetyl-CoA. The early steps of this pathway involve the sequential condensation of three acetyl-CoA molecules (3 x 2C) to form the biosynthetic intermediate mevalonate (MVA, 6C). 3-Hydroxy-3-methylglutaryl CoA reductase, which catalyzes the formation of MVA, is thought to be the rate-limiting enzyme in this pathway [59], although the... 

Mevalonic acid (MVA) is transformed into isopentenyl pyrophosphate (IPP) by decarboxylation, and is further transformed into dimethylallyl pyrophosphorate (DMAPP). IPP and DMAPP are the fundamental building blocks that are incorporated into terpenoids. Terpenoids are therefore regarded as compounds derived from the combination of multiple C5 units. These biosynthetic pathways are demonstrated by specific incorporation studies with T( H)- and C-labeled compounds [2-5],... 

Nomilin the general biosynthetic precursor of all limonoids, is biosynthesized via the terpenoid pathway from acetate and/or mevalonate in stems. Nomilin is then translocated to other plant tissues, including leaves, seeds, and fruit tissues, where it is converted to the other limonoids independently (Hasegawa et al. 1986 Ou et al. 1988). In most citrus species and hybrids, nomilin is converted to obacunone and then to obacunoate. Obacunaote is then converted to limonin probably via the intermediate ichangin. Nomilinic acid is the predominant acidic limonoid in citrus, but it does not seem to be directly involved in the biosynthetic pathways of major limonoids. 

As presented in this chapter, today, much is known about the process of terpene biosynthesis. The accumulated knowledge includes a detailed picture about the biosynthesis of the terpenoid monomers IPP and DMAPP either via the mevalonate or the DXP route and their interconversion by isomerases. Also, the stereochemical courses and enzyme mechanisms of all transformations have been largely elucidated. Especially the recently obtained structural data of prenyltransferases and various kinds of terpene synthases resulted in an evolutionary model that involves six domains (a, P, 7,8, e, and Q for the biosynthesis of linear polyisoprenoids from IPP and DMAPP and their subsequent transformation into (poly)cyclic terpenes. All these insights may open up new chances in controlling terpene biosynthesis, e.g., by directed evolution of terpene cyclases or domain swaps in multi-domain enzymes for the production of new terpenes, reconstitution of terpene biosynthetic pathways in heterologous hosts for production optimization, or targeted inhibitirm of pathways in pathogens for disease control. 

There are two biosynthetic pathways, (1) the mevalonate pathway and (2) the MEP/ DOXP pathway, responsible for the production of the terpenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which serve as the basis for the biosynthesis of molecules used in processes as diverse as terpenoid/ steroid/hormone synthesis, protein prenylation, protein anchoring, cell membrane maintenance, and N-glycosylation. 

BRs belong to the class of molecules known as triterpenoids. Because BRs are a group of modified sterols, the BR biosynthetic pathway can be divided into two major parts the sterol-specific pathway (which converts squalene to campesterol) and the BR-specific pathway (which converts campesterol to the BR). In the sterol-specific pathway, mevalonic acid (which is the starting material in terpenoid biosynthesis) is condensed and cyclized to produce 2,3-oxidosqualene. This precursor is further modified to form the major plant sterols such as sitosterol and campesterol. To become bioactive BRs, sterols must be processed by the BR-specific pathway. 

This completes our discussion of the phenols, the second largest group of secondary plant substances after the terpenoids. Listing the biosynthetic pathways in order of increasing importance for higher plants, phenols are formed by the acetate-mevalonate pathway, the acetate-malo-nate pathway, and, particularly, the shikimic acid pathway (Fig. 112). The cinnamic acids occupy a central position in phenol metabolism, participating as they do in the biosynthesis of all other important phenols. 

Biosynthetically, all terpenoids are traced back to a common synthon of biochemically active isoprene unit found in the forms of pyrophosphate esters either as dimeth-ylallyl diphosphate (DMAPP) or isopentenyl diphosphate (IPP) (Fig. 5.1). In turn, DMAPP and IPP are derived by two distinct biosynthetic pathways, the mevalonate pathway (MVA pathway) and the mevalonate-independent pathway or pathway of deoxyxylulose phosphate (DXP pathway), which are considered to be the major natural synthetic routes for the synthesis of terpenoids (Fig. 5.2). 

MVA and DXP biosynthetic pathways provide the essential active isopropene units in the form of IPP and DMAPP for the construction of natural terpenoids. Following this introduction, terpenoids have been organized in accordance to their major classifications into four subchapters, monoterpenes, sesquiterpenes, diterpenes, and higher terpenes. In each of these chapters, a detailed biosynthetic analysis is attempted. Thus, the current chapter serves only as an introduction and by any mean does not serve as an exhaustive review on the topic of mevalonic and deoxyxylulose biosynthetic pathways. 

Eicosanoids and terpenoids are still other classes of lipids. Eicosanoids, of which prostaglandins are the most abundant kind, are derived biosynthetically from arachidonic acid, are found in all body tissues, and have a wide range of physiological activity. Terpenoids are often isolated from the essential oils of plants, have an immense diversity of structure, and are produced biosynthetically from the five-carbon precursor isopentenyl diphosphate (IPP). lsopentenyl diphosphate is itself biosynthesized from 3 equivalents of acetate in the mevalonate pathway. 

Early attempts to reveal the biosynthetic route of ginkgolides, using [2- " C]-acetate and dl-[2- " C]-mevalonate, suggested the overall terpenoid origin of ginkgoUdes, and it was believed that ginkgolides were biosynthesized through the conventional mevalonate pathway." However, only recently it was reaUzed that the two conventional precursors, dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP), can participate in what is now known as the nonmevalonate pathway. 

All isoprenoids are biosynthesized from two isomeric 5-carbon compounds, isopentenyl diphosphate (IPP, 86) and dimethylallyl diphosphate (DMAPP, 87) (Fig. 11). The mammalian pathway for the biosynthesis of these key biosynthetic precursors from three acetyl-CoA units (83) via mevalonate (85) had been elucidated in the 1950s (51). In the wake of that pioneering work, it became established dogma that all terpenoids are invariably of mevalonate origin, even in the face of significant aberrant findings. 

Biosynthetic studies showed that the aromatic ring was formed from a poly-ketide whilst the side chain was derived from the mevalonate terpenoid pathway. The C-5 O-methyl and C-4 methyl groups were derived from methionine. The high incorporation of 4,6-dihydroxy-2,3-dimethyl-[l- C]benzoic acid (4.37) suggested that the methylation at C-4 occurred at the polyketide stage prior to the formation of the phthalide. 5,7-Dihydroxy-4-methyl-[7- C]phthalide (4.38) and its 6-farnesyl analogue were also incorporated eiSciently into mycophenolic acid. The farnesyl precursor was detected as a metabolite of P. brevi-compactum and shown to be formed from 5,7-dihydroxy-4-methyl-[7- C]phthalide by a trapping... 

Biosynthetically, majority of terpenoids are formed via the mevalonic acid, but they may also be formed through methyl-erythritol-4-phosphate (MEP) pathway. The C5 isoprene unit which can be linked together head to tail to form linear chains or cyclized to form rings is considered the building blocks of terpenes. Rather the C5 units exist as isopentenyl pyrophosphate or its isomer dimethylallyl pyrophosphate by enzymatic conversion and phosphorylation from mevalonic acid. The IPP may be considered as the precursor of hemiterpenes. In the biosynthesis of mono- and higher terpenes/terpenoids, the starting molecule is DMAPP, which... 

Dewick, P.M. (2001) The mevalonate and deoxyxylulose phosphate pathways terpenoids and steroids. In P.M. Dewick (ed.). Medicinal Natural Products A Biosynthetic Approach, 2nd edn. John WUey Sons Ltd., Chichester, pp. 167-289. 

---