Studies on the Biosynthesis of Fosfomycin. Conversion of 2-Hydroxyethylphosphonic Acid and 2-Aminoethylphosphonic Acid to Fosfomycin

Imai, Satoshi; Seto, Haruo; Ogawa, Hiroshi; Satoh, Atsuyuki; Ōtake, Noboru

doi:10.1080/00021369.1985.10866818

Cited by 6 publications

(5 citation statements)

References 2 publications

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“…A key to resolving this mechanistic puzzle was the early observation that 4 is efficiently converted to 9 by S. fradiae . , This was also the case with the mutant NP-7 strain of S. wemorensis that is defective in the biosynthesis of 2 . Initially 4 was thought to be a shunt product of 2 through reversible oxidation of the alcohol to the aldehyde by a nonspecific dehydrogenase. , However, this adventitious model was at odds with the observation that conversion of labeled [2- 18 O]- 4 by S. fradiae produces 9 that largely retains the 18 O label (50%) .…”

Section: Pathways For Synthesizing Complex Pn Natural Productsmentioning

confidence: 99%

Phosphonate Biochemistry

2016

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Organophosphonic acids are unique as natural products in terms of stability and mimicry. The C-P bond that defines these compounds resists hydrolytic cleavage, while the phosphonyl group is a versatile mimic of transition-states, intermediates, and primary metabolites. This versatility may explain why a variety of organisms have extensively explored the use organophosphonic acids as bioactive secondary metabolites. Several of these compounds, such as fosfomycin and bialaphos, figure prominently in human health and agriculture. The enzyme reactions that create these molecules are an interesting mix of chemistry that has been adopted from primary metabolism as well as those with no chemical precedent. Additionally, the phosphonate moiety represents a source of inorganic phosphate to microorganisms that live in environments that lack this nutrient; thus, unusual enzyme reactions have also evolved to cleave the C-P bond. This review is a comprehensive summary of the occurrence and function of organophosphonic acids natural products along with the mechanisms of the enzymes that synthesize and catabolize these molecules.

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Section: Pathways For Synthesizing Complex Pn Natural Productsmentioning

confidence: 99%

Phosphonate Biochemistry

2016

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“…One of these strains, Pseudomonas gladioli B-1, produced hydroxylethylphosphonic acid, known as a biosynthetic intermediate of fosfomycin (11), and PEPPM activity was detected in the cell extract of this strain. We report herein the purification and characterization of PEPPM from P. gladioli B-1.…”

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Purification and characterization of phosphoenolpyruvate phosphomutase from Pseudomonas gladioli B-1

et al. 1992

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Phosphoenolpyruvate phosphomutv-'^(PEPPM) catalyzes C-P bond formation by intramolecular rearrangement of phosphoenolpyruvate to pr fhonopyruvate (PnPy). We purified PEPPM from a gram-negative bacterium, Pseudomonas gladioli B isolated as a C-P compound producer. The equilibrium of this reaction favors the formation of the phosphate ester by deaving the C-P bond of PnPy, but the C-P bond-forming reaction is physiologically significant. The C-P bond-forming activity of PEPPM was confirmed with a purified protein. The molecular mass of the native enzyme was estimated to be 263 and 220 kDa by gel filtration and polyacrylamide gel electrophoresis, respectively. A subunit molecular mass of 61 kDa was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, indicating that the native protein was a tetramer.The optimum pH and temperature were 7.5 to 8.0 and 40°C, respectively. The K. value for PnPy was 19 ± 3.5 ,M, and the maximum initial velocity of the conversion of PnPy to phosphoenolpyruvate was 200 ,uM/s/mg. PEPPM was activated by the presence of the divalent metal ion, and the K. values were 3.5 ± 1.4 FM for Mge+, 16 + 5 nM for Mn+, 3.0 ± 1.5 PM for Zn2+, and 1.2 ± 0.2 P1M for Co2+.Since the discovery of the first natural C-P compound, 2-aminoethylphosphonic acid (10), various metabolites with C-P bonds have been isolated and the presence of phosphonates and phosphinates in a variety of biological systems has been established. Extensive studies on their unique C-P bond formation mechanisms (1,8, 9,20,23,24) indicated that the first step of the C-P bond formation pathway is the intramolecular rearrangement of phosphoenolpyruvate (PEP) to phosphonopyruvate (PnPy) and that the equilibrium of this reaction heavily favors the formation of the phosphate ester ( Fig.

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“…As an analog of phosphoenolpyruvate (PEP), this compound irreversibly inhibits PEP UDP-N-acetylglucosamine-3-O-enolpyruvyltransferase (enolpyruvyltransferase), which catalyzes the first step of peptidoglycan biosynthesis (8). Fosfomycin does not inhibit, however, other enzymes using PEP and shows almost no toxicity in humans (1,7).…”

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confidence: 99%

Characterization of the fomA and fomB Gene Products from Streptomyces wedmorensis , Which Confer Fosfomycin Resistance on Escherichia coli

Kobayashi

Kuzuyama

Seto

2000

Antimicrob Agents Chemother

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Together, the fomA and fomB genes in the fosfomycin biosynthetic gene cluster of Streptomyces wedmorensis confer high-level fosfomycin resistance on Escherichia coli. To elucidate their functions, the fomA and fomB genes were overexpressed in E. coli and the gene products were characterized. The recombinant FomA protein converted fosfomycin to fosfomycin monophosphate, which was inactive on E. coli, in the presence of a magnesium ion and ATP. On the other hand, the recombinant FomB protein did not inactivate fosfomycin. However, a reaction mixture containing FomA and FomB proteins converted fosfomycin to fosfomycin monophosphate and fosfomycin diphosphate in the presence of ATP and a magnesium ion, indicating that FomA and FomB catalyzed phosphorylations of fosfomycin and fosfomycin monophosphate, respectively. These results suggest that the self-resistance mechanism of the fosfomycin-producing organism S. wedmorensis is mono-and diphosphorylation of the phosphonate function of fosfomycin catalyzed by FomA and FomB.

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Studies on the Biosynthesis of Fosfomycin. Conversion of 2-Hydroxyethylphosphonic Acid and 2-Aminoethylphosphonic Acid to Fosfomycin

Cited by 6 publications

References 2 publications

Phosphonate Biochemistry

Phosphonate Biochemistry

Purification and characterization of phosphoenolpyruvate phosphomutase from Pseudomonas gladioli B-1

Characterization of the fomA and fomB Gene Products from Streptomyces wedmorensis , Which Confer Fosfomycin Resistance on Escherichia coli

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