Mevalonate-independent pathway

SCHEME 5.2 Deoxyxylulose phosphate pathway or mevalonate-independent pathway. 

Substrate binding pocket of IspF from E. coli consists of Ile57, Leu76, Ser35, Ser73, and Asp63 residues. 

Finally, a two electron reduction of cMEPP forms 2-methyl-2-( )-butenyl diphosphate followed by conversion to IPP and DMAPP. These steps are catalyzed by 1 -hydroxy-2-methyl-2-( )-butenyl-4-diphosphate synthase (IspG) [26] and 4-hydroxy-3-methyl-2-( )-butenyl-4-diphosphate reductase (IspH) [27], respectively. IspG and IspH enzymes possess [4Fe-4S] iron-sulfur redox cluster in their C-terminal domains, which represents the active center of the enzymes. The newest cocrystal structures of IspH from E. coli revealed the presence of a [4Fe-4S] cluster 

Animals appears to lack DXP pathway completely, thus formation of terpenes is exclusively produced by mevalonate pathway. It has to be pointed out that inhibitors of mevalonate pathway enzyme HMG-CoA reductase, like statins, do not affect the production of terpenoids by DXP pathway due to the absence of the particular enzyme in this metabolic pathway. On the other hand, it is possible to inhibit terpenoid production without affecting steroid formation by selectively inhibit DXP pathway in plants (e.g., fosmidomycin antibiotic) [5b, 28]. 

FROM ACETATE TO MEVALONATE AND DEOXYXYLULOSE PHOSPHATE BIOSYNTHETIC PATHWAYS 

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Rohmer, M., The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants, Nat. Prod. Rep., 16, 565, 1999. 

Sprenger, G.A. et al.. Identification of a thiamin-dependent synthase in Escherichia coli required for the formation of the 1-deoxy-D-xylulose 5-phosphate precursor to isoprenoids, thiamin, and pyridoxol, Proc. Natl. Acad Sci. USA 94, 12857, 1997. Lange, B.M. et al., A family of transketolases that directs isoprenoid biosynthesis via a mevalonate-independent pathway, Proc. Natl. Acad Sci. USA 95, 2100, 1998. Lois, L.M. et al., Cloning and characterization of a gene from Escherichia coli encoding a transketolase-like enzyme that catalyzes the synthesis of D-1- deoxyxylulose 5-phosphate, a common precursor for isoprenoid, thiamin, and pyridoxol biosynthesis, Proc. Natl. Acad. Sci. USA 95, 2105, 1998. 

The biosynthesis of monoterpenes, the major components of peppermint essential oils, can be divided into four stages (Fig. 9.4). Stage 1 includes the formation of isopentenyl diphosphate (IPP) and dimethylallyl alcohol (DMAPP). In plants, two separate pathways are utilized for the synthesis of these universal C5 intermediates, with the cytosolic mevalonate pathway being responsible for the formation of sterols and certain sesquiterpenes, and the plastidial mevalonate-independent pathway being involved in the biosynthesis of isoprene, monoterpenes, certain sesquiterpenes, diterpenes, tetraterpenes, as well as the side chains of chlorophyll and plastoquinone.16 In peppermint oil gland secretory cells, however, the mevalonate pathway is blocked and the biosynthesis of monoterpenoid essential... 

It had been suggested that the second step of the mevalonate-independent pathway involved an intramolecular rearrangement and subsequent reduction of DXP to yield 2-C-methyl-D-erythritol 4-phosphate (Fig. 9.6A).29-3 Seto and co-workers reported the isolation, by using a mutant complementation approach, and characterization of such a reductoisomerase gene from E. coli)2 Based on likely... 

As a first step, a method for the rapid and reproducible analysis of intermediates of the mevalonate-independent pathway was established. For all of... 

Carbohydrate phosphates Adenosine phosphates Intermediates of the mevalonate-independent pathway... 

Figure 9.7 Separation and detection of intermediates of the mevalonate-independent pathway of isoprenoid biosynthesis by LC-MS extracted ion chromatograms at (A) m/z 213 (1-deoxy-D-xylulose 5-phosphate), (B) m/z 215 (2-C-methyl-D-erythritol 4-phosphate), (C) m/z 520 (4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol), (D) m/z 600 (2-...

Table 9.2 Incorporation rate of [2-14C]-pyruvate into monoterpenes of isolated peppermint oil gland secretory cells in the presence of fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an enzyme of the mevalonate-independent pathway of isoprenoid biosynthesis.

The peppermint oil gland secretory cell cDNA library has proven to provide a highly enriched source of candidate genes involved in essential oil biosynthesis. A functional genomics approach has successfully been employed to clone genes involved in the mevalonate-independent pathway of isoprenoid biosynthesis and in the peppermint-specific steps producing (-)-menthol and (-)-menthone. The optimization of LC-MS technology to profile phosphoiylated carbohydrates and... 

LANGE, B.M., WILDUNG, M.R., McCASKILL, D., CROTEAU, R., A family of transketolases that directs isoprenoid biosynthesis via a mevalonate-independent pathway, Proc. Natl. Acad. Sci. USA, 1998, 95, 2100-2104. 

LICHTENTHALER, H.K., SCHWENDER, J., DISCH, A ROHMER, M., Biosynthesis of isoprenoids in higher plant chloroplasts proceeds via a mevalonate-independent pathway, FEBSLett., 1997, 400, 271-274... 

DUVOLD, T., BRAVO, J.-M., PALE-GROSDEMANGE, C., ROHMER, M., Biosynthesis of 2-C-methyl-D-erythritol, a putative C5 intermediate in the mevalonate independent pathway for isoprenoid biosynthesis, Tetrahedron Lett., 1997, 38, 4769-4772. 

More than half of the reported secondary metabolites from macroalgae are isoprenoids. Terpenes, steroids, carotenoids, prenylated quinines, and hydroqui-nones make up the isoprenoid class, which is understood to derive from either the classical mevalonate pathway, or the mevalonate-independent pathway (Stratmann et al. 1992). Melavonic acid (MVA) (Fig. 1.2) is the first committed metabolite of the terpene pathway. Dimethylallyl (dl meth al lal) pyrophosphate (DMAPP) (Fig. 1.3) and its isomer isopentenyl pyrophosphate (IPP, Fig. 1.3) are intermediates of the MVA pathway and exist in nearly all life forms (Humphrey and Beale 2006). Geranyl (ja ran al) (C10) and famesyl (C15) units are generated by head-to-tail (Fig. 1.3) condensation of two (for C10) or three (for C15) 5-carbon DMA-like isoprene units, identifiable in final products by the characteristic fish-tail repeating units, as traced over the structure of a sesquiterpene in Fig. 1.3 (Humphrey and Beale 2006). Additional IPP condensation with famesyl pyrophosphate (FPP)... 

The mevalonate-independent pathway is present in most bacteria and all phototropic organisms. In higher plants and most algae both pathways run independently. The mevalonate pathway is located in the cytoplasm and is responsible for the biosynthesis of most sesquiterpenoids. The mevalonate-independent pathway, in contrast, is restricted to the chloroplasts where plastid-related isoprenoids such as monoterpenes and diterpenes are biosynthesised via this pathway [43-45]. Figure 4.2 illustrates the interrelationships of both biosynthetic pathways connected to Fig. 4.1 [46]. 

Functionalized terpenes are the typical secondary metabolites of green alga, and their ecological roles have been well investigated. In principle, these metabolites could be derived either via the classical mevalonate pathway or the newly discovered mevalonate-independent pathway 86 however,... 

One of the more exciting and recent advances in the field of plant biochemistry has been the discovery of the mevalonate-independent pathway for the biosynthesis of isoprenoids (Fig. 10.4). This new pathway, referred to a the methyl-erythritol-phosphate or MEP pathway for the first intermediate committed solely to the biosynthesis of isoprenoids, was first discovered in prokaryotes capable of accumulating hopenes, the equivalent of eukaryotic sterols. 6,17 The MEP pathway has since been confirmed in plants and, not surprisingly, has been localized to chloroplasts.18 Operation of the MEP pathway is intimately related to the reactions of CO2 fixation and photosynthesis, as evidenced by the two immediate precursors pyruvate and phosphoglyceraldehyde for this pathway. Two important features of this pathway are that mevalonate is not an intermediate in the plastidic synthesis of isopentenyl (IPP) and dimethylallyl diphosphate, (DMAPP), and this pathway... 

Lange, B.M., and Croteau, R. (1999). Isopentenyl diphosphate biosynthesis via a mevalonate-independent pathway isopentenyl monophosphate kinase catalyzes the terminal enzymatic step. Proc Natl Acad Sci USA 96 13714-13719. 

E. coli and other Gram-negative bacteria synthesize the IPP and dimethylallyl diphosphate (DMAPP) by the mevalonate-independent pathway, also known as the nonmevalonate pathway (other names are deoxyxylulose phosphate or methylerythritol phosphate pathway). In contrast. Gram-positive bacteria and eukaryotes, including yeast, synthesize the side chain precursors by the mevalonate pathway. Interestingly, Streptomycetes possess both the mevalonate and nonmevalonate pathways. These pathways are the subject of Chapters 1.12, 1.13, 1.14, 1.22. 

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