Studies on the nonmevalonate pathway: formation of 2-C-methyl-d-erythritol 2,4-cyclodiphosphate from 2-phospho-4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol

Takagi, Motoki; Kuzuyama, Tomohisa; Kaneda, Kazuhide; Watanabe, Hiroyuki; Dairi, Tohru; Seto, Haruo

doi:10.1016/s0040-4039(00)00375-0

Cited by 97 publications

(76 citation statements)

References 12 publications

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“…In the next step, 2C-methyl-D-erythritol 4-phosphate is converted into the 2C-methyl-D-erythritol 2,4-cyclodiphosphate by the sequential action of three enzymes specified by the ispD, ispE, and ispF genes (19)(20)(21)(22)(23)(24). The last known step of the sequence, the reductive transformation of the cyclic diphosphate into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate has been identified recently in work with a recombinant Escherichia coli strain engineered for hyperexpression of the ispG gene (previously designated gcpE) (25).…”

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Studies on the nonmevalonate terpene biosynthetic pathway: Metabolic role of IspH (LytB) protein

Rohdich

Hecht²,

Gärtner³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

315

231

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Isopentenyl diphosphate and dimethylallyl diphosphate serve as the universal precursors for the biosynthesis of terpenes. Although their biosynthesis by means of mevalonate has been studied in detail, a second biosynthetic pathway for their formation by means of 1-deoxy-D-xylulose 5-phosphate has been discovered only recently in plants and certain eubacteria. Earlier in vivo experiments with recombinant Escherichia coli strains showed that exogenous 1-deoxy-Dxylulose can be converted into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate by the consecutive action of enzymes specified by the xylB and ispCDEFG genes. This article describes the transformation of exogenous [U-13 C5]1-deoxy-D-xylulose into a 5:1 mixture of [U-13 C5]isopentenyl diphosphate and [U-13 C5]dimethylallyl diphosphate by an E. coli strain engineered for the expression of the ispH (lytB) gene in addition to recombinant xylB and ispCDEFG genes.T erpenes are one of the largest groups of natural products comprising numerous medically relevant compounds (e.g., vitamins, hormones, and antitumor agents such as Taxol) (1). Bloch, Lynen, Cornforth, and their coworkers showed that the universal terpenoid precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), are biosynthesized by means of the mevalonate pathway in yeasts and animals (for review see refs. 2-5). These studies served as the basis for the development of metabolic inhibitors that are widely used for the treatment of hypercholesterolemia.For a period of several decades, these milestone achievements completely eclipsed the existence of a second terpenoid pathway for the biosynthesis of IPP and DMAPP. Recently, however, knowledge on that pathway has been unfolding rapidly on the basis of seminal discoveries by the research groups of . Briefly, the mevalonate independent pathway starts from 1-deoxy-D-xylulose 5-phosphate, which is assembled from pyruvate and D-glyceraldehyde 3-phosphate (13, 14) and was already known to serve as a biosynthetic precursor of vitamins B 1 (thiamine) and B 6 (pyridoxal) (Fig. 1) (15-17). 1-Deoxy-D-xylulose 5-phosphate is converted into 2C-methyl-D-erythritol 4-phosphate, the first committed intermediate of the nonmevalonate pathway, by isomerization followed by a two-electron reduction step catalyzed by 2C-methyl-D-erythritol 4-phosphate synthase specified by the ispC gene (formerly designated yaeM and then dxr) (18) (Fig. 1).In the next step, 2C-methyl-D-erythritol 4-phosphate is converted into the 2C-methyl-D-erythritol 2,4-cyclodiphosphate by the sequential action of three enzymes specified by the ispD, ispE, and ispF genes (19-24). The last known step of the sequence, the reductive transformation of the cyclic diphosphate into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate has been identified recently in work with a recombinant Escherichia coli strain engineered for hyperexpression of the ispG gene (previously designated gcpE) (25). Comparative genomics suggest that the protein specified by the lytB gene is involved in the conversion of ...

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confidence: 99%

Studies on the nonmevalonate terpene biosynthetic pathway: Metabolic role of IspH (LytB) protein

Rohdich

Hecht²,

Gärtner³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

315

231

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“…1). Next, CDP-ME2P is converted to 2C-methyl-D-erythritol-2,4-cyclodiphosphate and CMP (18,19). The cyclodiphosphate then, in two enzyme-catalyzed stages, undergoes reduction and elimination to 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate and onto IPP and DMAPP (20)(21)(22)(23).…”

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Biosynthesis of isoprenoids: Crystal structure of 4-diphosphocytidyl-2C-methyl- d -erythritol kinase

Miallau

Alphey

Kemp

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

109

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4-Diphosphocytidyl-2C-methyl-D-erythritol kinase, an essential enzyme in the nonmevalonate pathway of isopentenyl diphosphate and dimethylallyl diphosphate biosynthesis, catalyzes the single ATP-dependent phosphorylation stage affording 4-diphosphocytidyl-2C-methyl-D-erythritol-2-phosphate. The 2-Å resolution crystal structure of the Escherichia coli enzyme in a ternary complex with substrate and a nonhydrolyzable ATP analogue reveals the molecular determinants of specificity and catalysis. The enzyme subunit displays the ␣͞␤ fold characteristic of the galactose kinase͞ homoserine kinase͞mevalonate kinase͞phosphomevalonate kinase superfamily, arranged into cofactor and substrate-binding domains with the catalytic center positioned in a deep cleft between domains. Comparisons with related members of this superfamily indicate that the core regions of each domain are conserved, whereas there are significant differences in the substrate-binding pockets. The nonmevalonate pathway is essential in many microbial pathogens and distinct from the mevalonate pathway used by mammals. The high degree of sequence conservation of the enzyme across bacterial species suggests similarities in structure, specificity, and mechanism. Our model therefore provides an accurate template to facilitate the structure-based design of broad-spectrum antimicrobial agents.galactose kinase͞homoserine kinase͞mevalonate kinase͞ phosphomevalonate kinase ͉ enzyme mechanism ͉ nonmevalonate ͉ phosphorylation T he AT P-dependent 4-diphosphocytidyl-2C-methyl-Derythritol (CDP-ME) kinase (EC 2.7.1.148) participates in the biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). These isomers are the universal five-carbon precursors of isoprenoids, a diverse and important family of natural products that includes sterols, dolichols, triterpenes, and ubiquinones, and components of macromolecules such as the prenyl groups of prenylated proteins and isopentenylated tRNAs (1-3). Isoprenoids contribute to many biological functions, including electron transport in respiration and photosynthesis, hormone-based signaling, apoptosis, meiosis, protein cleavage, and degradation (4). In addition, they provide important structural components of cell membranes (1).Two biosynthetic routes to IPP and DMAPP have evolved. In eukaryotes, archaebacteria, and a few eubacteria, the precursor biosynthesis is through the mevalonate pathway (3-7). This begins with the conversion of three molecules of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA followed by reduction, phosphorylation, and decarboxylation to generate IPP, some of which is isomerized to DMAPP. The last three steps in this pathway are ATP-dependent and catalyzed by the structurally related mevalonate kinase (MVK), phosphomevalonate kinase, and mevalonate 5-diphosphate decarboxylase.In chloroplasts, algae, cyanobacteria, most eubacteria, and the apicomplexa, IPP and DMAPP synthesis is accomplished by seven enzymes in a pathway named after one of the intermediates, the 1-deoxy-D-xylulose-5-ph...

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“…14, 15). Next, CDP-ME2P is converted to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP) by the action of MECDP synthase (16,17). However, the subsequent reactions leading to the formation of IPP from MECDP remain to be elucidated.…”

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An unusual isopentenyl diphosphate isomerase found in the mevalonate pathway gene cluster from Streptomyces sp. strain CL190

Kaneda¹

2001

Proceedings of the National Academy of Sciences

137

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A gene cluster encoding five enzymes of the mevalonate pathway had been cloned from Streptomyces sp. strain CL190. This gene cluster contained an additional ORF, orfD, encoding an unknown protein that was detected in some archaebacteria and some Grampositive bacteria including Staphylococcus aureus. The recombinant product of orfD was purified as a soluble protein and characterized. The molecular mass of the enzyme was estimated to be 37 kDa by SDS-polyacrylamide gel electrophoresis and 155 kDa by gel filtration chromatography, suggesting that the enzyme is most likely to be a tetramer. The purified enzyme contained flavin mononucleotide (FMN) with the amount per tetramer being 1.4 to 1.6 mol͞mol. The enzyme catalyzed the isomerization of isopentenyl diphosphate (IPP) to produce dimethylallyl diphosphate (DMAPP) in the presence of both FMN and NADPH. The Escherichia coli plasmid expressing orfD could complement the disrupted IPP isomerase gene in E. coli. These results indicate that orfD encodes an unusual IPP isomerase showing no sequence similarity to those of IPP isomerases identified to date. Based on the difference in enzymatic properties, we classify the IPP isomerases into two types: Type 2 for FMN-and NAD(P)H-dependent enzymes, and type 1 for the others. In view of the critical role of this isomerase in S. aureus and of the different enzymatic properties of mammalian (type 1) and S. aureus (type 2) isomerases, this unusual enzyme is considered to be a suitable molecular target for the screening of antibacterial drugs specific to S. aureus.I soprenoids play important roles in all living organisms; they function as steroid hormones in mammals, carotenoids in plants, and ubiquinone or menaquinone in bacteria (1). All of these isoprenoids are synthesized by consecutive condensations of the five-carbon precursor isopentenyl diphosphate (IPP) to its isomer dimethylallyl diphosphate (DMAPP). Two distinct pathways for the IPP biosynthesis are known. One is the mevalonate pathway that operates in eukaryotes, archaebacteria, and the cytosols of higher plants. The other is the nonmevalonate pathway ( Fig. 1), which is generally used by many eubacteria, including Escherichia coli and Bacillus subtilis, green algae, and the chloroplasts of higher plants (2, 3). The initial step of this pathway is the formation of 1-deoxy-D-xylulose 5-phosphate (DXP) by condensation of pyruvate and glyceraldehyde 3-phosphate catalyzed by DXP synthase (4-7). In the second step, DXP is converted to 2-C-methyl-D-erythritol 4-phosphate (MEP) by DXP reductoisomerase (8-11). MEP is then cytidylylated by MEP cytidylyltransferase to give 4-(cytidine 5Ј-diphospho)-2-Cmethyl-D-erythritol (CDP-ME) (12, 13), which is phosphorylated by CDP-ME kinase to yield 2-phospho-4-(cytidine 5Ј-diphospho)-2-C-methyl-D-erythritol (CDP-ME2P; refs. 14, 15). Next, CDP-ME2P is converted to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (MECDP) by the action of MECDP synthase (16,17). However, the subsequent reactions leading to the formation of IPP from MECDP remain...

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Studies on the nonmevalonate pathway: formation of 2-C-methyl-d-erythritol 2,4-cyclodiphosphate from 2-phospho-4-(cytidine 5′-diphospho)-2-C-methyl-d-erythritol

Cited by 97 publications

References 12 publications

Studies on the nonmevalonate terpene biosynthetic pathway: Metabolic role of IspH (LytB) protein

Studies on the nonmevalonate terpene biosynthetic pathway: Metabolic role of IspH (LytB) protein

Biosynthesis of isoprenoids: Crystal structure of 4-diphosphocytidyl-2C-methyl- d -erythritol kinase

An unusual isopentenyl diphosphate isomerase found in the mevalonate pathway gene cluster from Streptomyces sp. strain CL190

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