Mevalonate pathway, terpenoid

The terpenoid precursor isopentenyl diphosphate, formerly called isopentenyl pyrophosphate and abbreviated IPP, is biosynthesized by two different pathways depending on the organism and the structure of the final product. In animals and higher plants, sesquiterpenoids and triterpenoids arise primarily from the mevalonate pathway, whereas monoterpenoids, diterpenoids, and tetraterpenoids are biosynthesized by the 1-deoxyxylulose 5-phosphate (DXP) pathway. In bacteria,... 

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. 

The late cannabinoid pathway starts with the alkylation of ohvetolic acid (3.2 in Fig. 4) as polyketide by geranyl diphosphate (3.1) as the terpenoid unit. Terpenoids can be found in all organisms, and in plants two terpenoid pathways are known, the so called mevalonate (MEV) and non-mevalonate (DXP) pathway as described by Eisenrich, lichtenthaler and Rohdich [23,24,29,30]. The mevalonate pathway is located in the cytoplasm of the plant cells [30], whereas the DXP pathway as major pathway is located in the plastids of the plant cells [29] and delivers geranyl diphosphate as one important precursor in the biosynthesis. 

Rohmer, M., Seemann, M., Horbach, S. et al. (1996) Glyceraldehyde 3-phosphate and pyruvate as precursors of isoprenic units in an alternative non-mevalonate pathway for terpenoid biosynthesis. Journal of the American... 

Dubey VS, Bhalla R, Luthra R (2003) An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants. J Biosci 28 637-646... 

Martin VJJ, Pitera DJ, Withers ST, Newman JD, Keasling JD. (2003) Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nature Biotechnol 21 796-802. 

In the 1970s the biosynthesis of cannabinoids was investigated with radiolabeling experiments. 14C-labeled mevalonate and malonate were shown to be incorporated into tetrahydrocannabinolic acid and cannabichromenic acid at very low rates (< 0.02%). Until 1990 the precursors of all terpenoids, isopentenyl diphosphate and dimethyl-allyl diphosphate were believed to be biosynthesized via the mevalonate pathway. Subsequent studies, however, proved that many plant terpenoids are biosynthesized via the recently discovered deoxyxylulose phosphate pathway (Eisenreich et al., 1998 Rohmer, 1999). It was shown that the Cio-terpenoid moiety of cannabinoids is biosynthesized entirely or predominantly (>98%) via this pathway (Fellermeister et al., 2001). The phenolic moiety is generated by a polyketide-type reaction sequence. 

There are diffent pathways by which all phenolic compounds are synthesized [6,7]. The shikimate/arogenate pathway leads, through phenylalanine, to the majority of plant phenolics, and therefore we shall centre the present revision on the detailed description of this pathway. The acetate/malonate pathway leads to some plant quinones but also to various side-chain-elongated phenylpropanoids (e.g. the group of flavonoids). Finally, the acetate/mevalonate pathway leads by dehydrogenation reactions to some aromatic terpenoids. 

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. 

Figure 5.3 Outline of the mevalonate pathway for the formation of C5 isoprenoid units. Most research has focused on HMC-CoA reductase (HMCR), the rate-determining step in terpenoid biosynthesis in mammals. P indicates a phosphate moiety. HMC-CoA, 3-hydroxy-3 methylglutaryl coenzyme A NADPH, nicotinamide adenine dinucleotide phosphate (reduced form) SCoA, S-Coenzyme A (to which acetate is attached) CoASH, free coenzyme A.

The existence of a similar non-mevalonate route to terpenoids in plants was first reported in 1994. When Duilio Arigoni and co-workers fed different C-labelled forms of glucose to Ginkgo biloba embryos, the G-nuclear magnetic resonance (NMR) spectra of the resulting diterpenes were not what would have been expected from the normal operation of the mevalonate pathway (Cartayrade et al, 1994), but showed an incorporation pattern identical to that seen with the E. coli terpenoids. Subsequent studies employing... 

Mevalonic acid, a six-carbon building block, is made up from three molecules of the most basic two-carbon precursor, acetyl-CoA. The mevalonate pathway, which involves the intermediary of mevalonic acid, directs acetate into a series of natural products different from those derived directly from the acetate pathway and includes terpenoids and steroids. Terpenoids constitute the most chemically diverse and one of the largest groups of plant natural products, and therefore a detailed discussion on this group of natural products is warranted. 

Jux A, Gleixner G, Boland W. Classification of terpenoids according to the methylerythritol phosphate or the mevalonate pathway with natural C/ C ratios dynamic allocation of resources in induced plants. Angew. Chem. Int. Ed. 2001 40 2091-2093. 

Terpenoids are derived from the cytosolic mevalonate pathway or from the plastidial 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway (see also Terpenoid Biosynthesis). Both pathways lead to the formation of the C5 units isopentenyl diphosphate and its allylic isomer dimethylallyl diphosphate, which are the basic terpenoid biosynthesis building blocks (Fig. 1). Although increasing evidence suggests that exchange of intermediates occurs between these compartments, the cytoplasmic mevalonate pathway is generally considered to supply the precursors for the production of sesquiterpenes and triterpenes (including sterols) and to provide precursors for protein prenylation and for ubiquinone and heme-A production in mitochondria. In the plastids, the MEP pathway supplies the precursors for the production of isoprene, monoterpenes, diterpenes (e.g., GAs), and tetraterpenes (e.g., carotenoids). 

Mevalonate diphosphate decarboxylase (MVP EC4.1.1.33) catalyzes the conversion of mevalonate diphosphate to isopentenyl diphosphate, a key building block for a large family of functionally important terpenoids. Fig. (6). This reaction is the third step in the biosynthesis of steroids and terpenoids from the mevalonate pathway, and the last well characterized step in the mevalonate pathway for the biosynthesis of isopentenyl pyrophophaste, the isoprenoids precursor [296-298]. Some reports showed that MVP is located predominantly in the cytosolic fraction and its expression is independent of peroxisome proliferation [299-300]. 

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