Nonmevalonate pathway

Hsieh, M.H. and Goodman, H.M., The Arabidopsis IspH homolog is involved in the plastid nonmevalonate pathway of isoprenoid biosynthesis, Plant Physiol. 138, 641, 2005. 

TAKAHASHI, S., KUZUYAMA, T WATANABE H., SETO, H., A 1-deoxy-D-xylulose 5-phosphate reductoisomerase catalyzing the formation of 2-C-methyl-D-erythritol 4-phosphate in an alternative nonmevalonate pathway, Proc. Natl. Acad. Sci. USA, 1998, 95, 9879-9884. 

KUZUYAMA, T., TAKAGI, M., KANEDA, K, WATANABE, H, DAIRI, T., SETO, H., Studies on the nonmevalonate pathway conversion of 4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol to its 2-phospho derivative by 4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol kinase, Tetrahedron Lett., 2000, 41, 2925-2928. 

Thiamin is synthesized in bacteria, fungi, and plants from 1-deoxyxylulose 5-phosphate (Eq. 25-21), which is also an intermediate in the nonmevalonate pathway of polyprenyl synthesis. However, thiamin diphosphate is a coenzyme for synthesis of this intermediate (p. 736), suggesting that an alternative pathway must also exist. Each of the two rings of thiamin is formed separately as the esters 4-amino-5-hydroxy-methylpyrimidine diphosphate and 4-methyl-5-((i-hydroxyethyl) thiazole monophosphate. These precursors are joined with displacement of pyrophosphate to form thiamin monophosphate.92b In eukaryotes this is hydrolyzed to thiamin, then converted to thiamin diphosphate by transfer of a diphospho group from ATP.92b c In bacteria thiamin monophosphate is converted to the diphosphate by ATP and thiamin monophosphate kinase.92b... 

Figure 12 Mevalonate pathway and nonmevalonate pathway. Antibiotic fosmidomycin inhibits 1-deoxy-D-xylulose 5-phosphate (DXP) reductoisomerase.

T Kuzuyama, T Shimizu, S Takahashi, H Seto. Fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway for terpenoid biosynthesis. Tetrahedron Lett 39 7913-7916, 1998. 

H Jomaa, J Wiester, S Sanderbrand, B Altincicek, C Weidemeyer, M Hintz, I Tur-bachova, M Eberl, J Zeidler, HK Lichtenthaler, D Soldati, E Beck. Inhibitors of nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285 1573-1576, 1999. 

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. 

Kuzuyama, T. (2002) Mevalonate and nonmevalonate pathways for the biosynthesis of isoprene units. Biosci. Biotechnol Biochem., 66,1619-27. 

In bacteria, the thiazole moiety (42) of thiamine is derived from 1-deoxy-D-xylulose 5-phosphate (43) that can also serve as a precursor for pyridoxal in many eubacteria (Fig. 5) and for isoprenoids via the nonmevalonate pathway (cf. isoprenoid cofactors). The sulfur atom is derived from the persulfide that also serves as precursor for iron/sulfur clusters and for biotin (6) and thiooctanoate (7) (Fig. 1). C2 and N3 of the thiazole moiety of thiamine have been reported to stem from tyrosine in Escherichia coli and from glycine in Bacillus subtilis, respectively. Yeasts use ADP-ribulose (44) derived from NAD as precursor (24). 

The existence of a second pathway that affords IPP and DMAPP was discovered in the 1990s. The details of that non-mevalonate pathway were then established in rapid sequence by the combination of isotope studies, comparative genomics, and enzymology (52). The delayed discovery of the nonmevalonate pathway can serve as paradigm for pitfalls in the elucidation of biosynthetic pathways. 

The mevalonate pathway starts with a sequence of two Claisen condensations that afford (6 )-3-hydroxy-3-methyl-glutaryl-CoA (84) from three acetyl-CoA moieties. The pathway affords IPP that can be converted into DMAPP by isomerization. The first committed intermediate of the nonmevalonate pathway is 2C-methyl-D-erythritol 4-phosphate (90) obtained from 1-deoxy-D-xylulose 5-phosphate (43), which is a compound also involved in the biosynthesis of vitamins Bi (46, cf. Fig. 4) and Be (39, cf. Fig. 5), by rearrangement and subsequent reduction. Three enzyme-catalyzed steps are required to convert the compound into the cognate cyclic diphosphate 91 that is then converted reductively into a mixture of IPP and DMAPP by the consecutive action of two iron/sulfur proteins. 

Branching of pathways is relevant in several cases. Thus, intermediates of the porphyrin biosynthetic pathway serve as precursors for chlorophyll (17, Fig. 2) and for the corrinoid ring systems of vitamin B12 (20, Fig. 2) (17). 1-Deoxy-D-xylulose 5-phosphate (43) serves as an intermediate for the biosynthesis of pyridoxal 5 -phosphate (39, Fig. 5), for the terpenoid precursor IPP (86) via the nonmevalonate pathway (Fig. 11), and for the thiazole moiety of thiamine pyrophosphate (46, Fig. 4). 7,8-Dihydroneopterin triphosphate (29, Fig. 3) serves as intermediate in the biosynthetic pathways of tetrahydrofolate (33) and tetrahydrobiopterin (31). The closely related compound 7,8-dihydroneopterin 2, 3 -cyclic phosphate is the precursor of the archaeal cofactor, tetrahydromethanopterin (34) (58). A common pyrimidine-type intermediate (23) serves as precursor for flavin and deazaflavin coenzymes. Various sulfur-containing coenzymes (thiamine (9), lipoic acid (7), biotin (6), Fig. 1) use a pyrosulfide protein precursor that is also used for the biosynthesis of inorganic sulfide as a precursor for iron/sulfur clusters (12). 

Fosmidomycin, initially discovered as a product of Strepto-myces lavendulae with antibacterial and herbicide activity, was recently shovm to act via the inhibition of IspC protein that catalyzes the first committed step in the nonmevalonate pathway of isoprenoid biosynthesis that is absent in humans (43 90, Fig. 11). Based on these findings, the compound is now under clinical evaluation as an antimalarial drug (78). 

Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Tiirbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 1999 285 1573-1576. 

Dudareva N, Andersson S, Orlova I, Gatto N, Reichelt M, Rhodes D, Boland W, Gershenzon J. The nonmevalonate pathway supports both monoterpene and sequiterpene formation in snapdragon flowers. Proc. Natl. Acad. Sci. U.S.A. 2005 102 933-938. 

A second pathway for the biosynthesis of IPP and DMAPP eluded discovery until the 1990s but was then rapidly elucidated in considerable detail (deoxyxylulose pathway, Figure 8). These events have been reviewed repeatedly and will not be discussed at this point suffice it to say that retrobiosynthetic analysis has been involved to some extent in the elucidation of the nonmevalonate pathway (specific examples are given in Eisenreich et al.51). 

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. 

The formation of IPP/DMAPP via an alternative, nonmevalonate, pathway has been described (93). In this pathway, a TPP-activated acetaldehyde (generated by pyruvate decarboxylation) is coupled to the C-2 carbonyl... 

Rohmer M (1999) The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat Prod Rep 16 565-574 Kazuyama T (2002) Mevalonate and nonmevalonate pathways for the biosynthesis of isoprene units. Biosci Biotechnol Biochem 66 1619-1627... 

Kuzuyama T, Takagi M, Takahashi S, Seto H (2000) Cloning and characterization of 1-deoxy-D-xylulose 5-phosphate synthase from Streptomyces sp. Strain CL190, which uses both the mevalonate and nonmevalonate pathways for isopentenyl diphosphate biosynthesis. J Bacteriol 182 891... 

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