Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis

Zhao, Lishan; Chang, Wei‐chen; Xiao, Youli; Liu, Hung Wen; Liu, Pinghua

doi:10.1146/annurev-biochem-052010-100934

Cited by 276 publications

(191 citation statements)

References 167 publications

(227 reference statements)

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“…IPP and DMAPP, derived from the acetate-mevalonate or methylerythritol phosphate pathway (Boronat and Rodriguez-Concepcion 2015;Chang et al 2013;Zhao et al 2013), serve as precursors for prenyl diphosphate (nxC 5 ) biosynthesis (Oldfield and Lin 2012). The prenyl diphosphates can be used for the biosynthesis of different terpenoids by cyclization and oxidation or as prenyl donors for peptide, protein and tRNA prenyltransferases, or aromatic prenyltransferases.…”

Section: Classification Of Prenyltransferasesmentioning

confidence: 99%

Prenyltransferases as key enzymes in primary and secondary metabolism

Winkelblech

Fan

2015

Appl Microbiol Biotechnol

146

167

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Attachment of isoprene units to various acceptors by prenylation plays an important role in primary and secondary metabolism of living organisms. Protein prenylation belongs to posttranslational modification and is involved in cellular regulation process. Prenylated secondary metabolites usually demonstrate promising biological and pharmacological activities. Prenyl transfer reactions catalyzed by prenyltransferases represent the key steps in the biosynthesis and contribute significantly to the structural and biological diversity of these compounds. In the last decade, remarkable progress has been achieved in the biochemical, molecular, and structural biological investigations of prenyltransferases, especially on those of the members of the dimethylallyltryptophan synthase (DMATS) superfamily. Until now, more than 40 of such soluble enzymes are identified and characterized biochemically. They catalyze usually regioselective and stereoselective prenylations of a series of aromatic substances including tryptophan, tryptophan-containing peptides, and other indole derivatives as well as tyrosine or even nitrogen-free substrates. Crystal structures of a number of prenyltransferases have been solved in the past 10 years and provide a solid basis for understanding the mechanism of prenyl transfer reactions.

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Section: Classification Of Prenyltransferasesmentioning

confidence: 99%

Prenyltransferases as key enzymes in primary and secondary metabolism

Winkelblech

Fan

2015

Appl Microbiol Biotechnol

146

167

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“…In most eubacteria IPP and DMAPP biosynthesis proceed exclusively through the methylerythritol 4-phosphate (MEP) pathway [2] [3]. In the first reaction pyruvate and D-glyceraldehyde 3-phosphate (GAP) are condensed to yield deoxyxylulose 5-phosphate (DXP).…”

Section: Introductionmentioning

confidence: 99%

Catalytically Important Residues in E. coli 1-Deoxy-D-Xylulose 5-Phosphate Synthase

Querol-Audí¹,

Boronat²,

Centelles³

et al. 2014

JBM

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1-deoxy-D-xylulose 5-phosphate synthase (DXS) catalyzes the initial step of the 2-C-methyl-Derythritol 4-phosphate (MEP)pathway consisting in the condensation of (hydroxiethyl)thiamin derived from pyruvate with D-glyceraldehyde 3-phosphate (GAP) to yield 1-deoxy-D-xylulose 5-phosphate (DXP). The role of the conserved residues H49, E370, D427 and H431 of E. coli DXS was examined by site-directed mutagenesis and kinetic analysis of the purified recombinant enzyme mutants. Mutants at position H49 showed a severe reduction in their specific activities with a decrease of the kcat/KM ratio by two orders of magnitude lower than the wild-type DXS. According to available structural data residue H49 is perfectly positioned to abstract a proton from the donor substrate. Mutations in DXS E370 showed that this residue is also essential for catalytic activity. Three-dimensional structure supports its involvement in cofactor deprotonation, the first step in enzymatic thiamin catalysis. Results obtained with H431 mutant enzymes indicate that this residue plays a role contributing to transition state stabilization. Finally, mutants at position D427 also showed a severe specific activity decrease with a reduction of the kcat/KM ratio. A role in binding the substrate and selecting the stereoisomer is proposed for D427.

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“…Notable isoprenoids include such critical molecules as chlorophyll, ubiquinone, and cholesterol. All isoprenoids are derived from a common set of precursors, the 5-carbon molecules isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP) (3). Both IPP and DMAPP are synthesized de novo by all free-living organisms, and a failure to produce these compounds is incompatible with life.…”

mentioning

confidence: 99%

Resistance to the Antimicrobial Agent Fosmidomycin and an FR900098 Prodrug through Mutations in the Deoxyxylulose Phosphate Reductoisomerase Gene ( dxr )

Armstrong

Meyers

Imlay

et al. 2015

Antimicrob Agents Chemother

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There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs.

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Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis

Cited by 276 publications

References 167 publications

Prenyltransferases as key enzymes in primary and secondary metabolism

Prenyltransferases as key enzymes in primary and secondary metabolism

Catalytically Important Residues in E. coli 1-Deoxy-D-Xylulose 5-Phosphate Synthase

Resistance to the Antimicrobial Agent Fosmidomycin and an FR900098 Prodrug through Mutations in the Deoxyxylulose Phosphate Reductoisomerase Gene ( dxr )

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