Biosynthesis of terpenoids: YgbB protein converts 4-diphosphocytidyl-2C-methyl-
            <scp>d</scp>
            -erythritol 2-phosphate to 2C-methyl-
            <scp>d</scp>
            -erythritol 2,4-cyclodiphosphate

Herz, Stefan; Wungsintaweekul, Juraithip; Schuhr, Christoph A.; Hecht, Stefan; Lüttgen, Holger; Sagner, Sylvia; Fellermeier, Monika; Eisenreich, Wolfgang; Zenk, Meinhart H.; Bacher, Adelbert; Rohdich, Felix

doi:10.1073/pnas.040554697

Cited by 238 publications

(196 citation statements)

References 23 publications

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“…Recently, a role in the DXP pathway has been proposed for another member of this superfamily, called YchB in E. coli (indicated by 12 in Fig. 1), which is capable of forming IPP by phosphorylation of an isopentenyl monophosphate (IMP) precursor, and also phosphorylates the essential intermediate phosphocytidyl-2-C-methylerythritol (Lange and Croteau 1999;Luttgen et al 2000). We found that related sequence motifs are present in diphosphomevalonate decarboxylases.…”

Section: Detailing the Motifs: New Sequence Relationships For Three Ementioning

confidence: 82%

Biosynthesis of Isoprenoids via Mevalonate in Archaea: The Lost Pathway

Smit

Mushegian²

2000

Genome Res.

124

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Isoprenoid compounds are ubiquitous in living species and diverse in biological function. Isoprenoid side chains of the membrane lipids are biochemical markers distinguishing archaea from the rest of living forms. The mevalonate pathway of isoprenoid biosynthesis has been defined completely in yeast, while the alternative, deoxy-D-xylulose phosphate synthase pathway is found in many bacteria. In archaea, some enzymes of the mevalonate pathway are found, but the orthologs of three yeast proteins, accounting for the route from phosphomevalonate to geranyl pyrophosphate, are missing, as are the enzymes from the alternative pathway. To understand the evolution of isoprenoid biosynthesis, as well as the mechanism of lipid biosynthesis in archaea, sequence motifs in the known enzymes of the two pathways of isoprenoid biosynthesis were analyzed. New sequence relationships were detected, including similarities between diphosphomevalonate decarboxylase and kinases of the galactokinase superfamily, between the metazoan phosphomevalonate kinase and the nucleoside monophosphate kinase superfamily, and between isopentenyl pyrophosphate isomerases and MutT pyrophosphohydrolases. Based on these findings, orphan members of the galactokinase, nucleoside monophosphate kinase, and pyrophosphohydrolase families in archaeal genomes were evaluated as candidate enzymes for the three missing steps. Alternative methods of finding these missing links were explored, including physical linkage of open reading frames and patterns of ortholog distribution in different species. Combining these approaches resulted in the generation of a short list of 13 candidate genes for the three missing functions in archaea, whose participation in isoprenoid biosynthesis is amenable to biochemical and genetic investigation.

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Section: Detailing the Motifs: New Sequence Relationships For Three Ementioning

confidence: 82%

Biosynthesis of Isoprenoids via Mevalonate in Archaea: The Lost Pathway

Smit

Mushegian²

2000

Genome Res.

124

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“…Partial reconstitution of the MEP pathway was performed essentially as described (20)(21)(22). Briefly, partially purified recombinant chlamydial IspD, IspE, and IspF, dialyzed in a 10,000 molecular weight cut-off dialysis cassette (Pierce) against a 20 mM Tris⅐HCl, pH 6.8͞50 mM NaCl solution to remove any contaminating small molecules, were sequentially added to reaction mixtures containing 5 mM CTP, 5 mM ATP, 1 mM DTT, 10 mM MgCl 2 , and 100 mM Tris⅐HCl at pH 6.8, in the presence or absence of 12 M MEP.…”

Section: Methodsmentioning

confidence: 99%

Chlamydial histone-DNA interactions are disrupted by a metabolite in the methylerythritol phosphate pathway of isoprenoid biosynthesis

Grieshaber

Fischer

Mead

et al. 2004

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

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The chlamydial developmental cycle is characterized by an intracellular replicative form, termed the reticulate body, and an extracellular form called the elementary body. Elementary bodies are characterized by a condensed chromatin, which is maintained by a histone H1-like protein, Hc1. Differentiation of elementary bodies to reticulate bodies is accompanied by dispersal of the chromatin as chlamydiae become transcriptionally active, although the mechanisms of Hc1 release from DNA have remained unknown. Dissociation of the nucleoid requires chlamydial transcription and translation with negligible loss of Hc1. A genetic screen was therefore designed to identify chlamydial genes rescuing Escherichia coli from the lethal effects of Hc1 overexpression. CT804, a gene homologous to ispE, which encodes an intermediate enzyme of the non-mevalonate methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, was selected. E. coli coexpressing CT804 and Hc1 grew normally, although they expressed Hc1 to a level equivalent to that which condensed the chromatin of parent Hc1-expressing controls. Inhibition of the MEP pathway with fosmidomycin abolished IspE rescue of Hc1-expressing E. coli. Deproteinated extract from IspE-expressing bacteria caused dispersal of purified chlamydial nucleoids, suggesting that chlamydial histone-DNA interactions are disrupted by a small metabolite within the MEP pathway rather than by direct action of IspE. By partial reconstruction of the MEP pathway, we determined that 2-C-methylerythritol 2,4-cyclodiphosphate dissociated Hc1 from chlamydial chromatin. These results suggest that chlamydial histone-DNA interactions are disrupted upon germination by a small metabolite in the MEP pathway of isoprenoid biosynthesis.C hlamydia trachomatis is the leading cause of preventable blindness worldwide and a major cause of sexually transmitted disease in developed countries (1). Chlamydiae are bacterial obligate intracellular pathogens with a biphasic developmental cycle that alternates between infectious extracellular forms, termed elementary bodies (EBs), and intracellular replicative forms known as reticulate bodies (RBs) (2). The metabolically inert EBs are characterized by a condensed nucleoid structure. Within a few hours after infection the chromatin becomes dispersed as transcription is initiated and differentiation to the larger, metabolically active RBs begins (3). RBs replicate by binary fission until 18 to 48 h after infection, at which time they begin to differentiate back to EBs, a process typified by recompaction of the nucleoid.The DNA of EBs is held in a condensed state by the action of two histone H1 homologs, Hc1 and Hc2 (4-8). Hc1 is conserved among all chlamydiae, whereas Hc2 displays a variable molecular weight depending on the C. trachomatis serovar and is absent from some chlamydial species and strains (5). Both hctA and hctB, encoding Hc1 and Hc2, respectively, are transcribed late in the developmental cycle concomitant with RB differentiation back to EBs and nucleoid cond...

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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).…”

mentioning

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.

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315

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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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Biosynthesis of terpenoids: YgbB protein converts 4-diphosphocytidyl-2C-methyl- d -erythritol 2-phosphate to 2C-methyl- d -erythritol 2,4-cyclodiphosphate

Cited by 238 publications

References 23 publications

Biosynthesis of Isoprenoids via Mevalonate in Archaea: The Lost Pathway

Biosynthesis of Isoprenoids via Mevalonate in Archaea: The Lost Pathway

Chlamydial histone-DNA interactions are disrupted by a metabolite in the methylerythritol phosphate pathway of isoprenoid biosynthesis

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

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