Stereochemical investigations have shown that the conversion of 2-hydroxyethylphosphonate to hydroxymethylphosphonate by the enzyme HEPD involves removal of the pro-S hydrogen at C2 and, surprisingly, the loss of stereochemical information at C1. As a result, the mechanisms previously proposed for HEPD must be re-evaluated.
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Characterization of the cobalamin-dependent radical S-adenosyl-l-methionine enzyme C-methyltransferase Fom3 in fosfomycin biosynthesis.
Methods Enzymol
June 2022
Department of Chemistry, Tokyo Institute of Technology, Tokyo, Japan. Electronic address:
Fosfomycin is a clinically used broad-spectrum antibiotic that has the structure of an oxirane ring with a phosphonic acid substituent and a methyl substituent. In nature, fosfomycin is produced by Streptomyces spp. and Pseudomonas sp.
View Article and Find Full Text PDFFom3, the antepenultimate enzyme in the fosfomycin biosynthetic pathway in Streptomyces spp., is a class B cobalamin-dependent radical SAM methyltransferase that catalyzes methylation of (5'-cytidylyl)-2-hydroxyethylphosphonate (2-HEP-CMP) to form (5'-cytidylyl)-2-hydroxypropylphosphonate (2-HPP-CMP). Previously, the reaction of Fom3 with 2-HEP-CMP produced 2-HPP-CMP with mixed stereochemistry at C2.
View Article and Find Full Text PDFC-Methylation Catalyzed by Fom3, a Cobalamin-Dependent Radical S-adenosyl-l-methionine Enzyme in Fosfomycin Biosynthesis, Proceeds with Inversion of Configuration.
Biochemistry
August 2018
Department of Chemistry , Tokyo Institute of Technology, 2-12-1 O-okayama , Meguro-ku, Tokyo 152-8551 , Japan.
Fom3, a cobalamin-dependent radical S-adenosyl-l-methionine (SAM) methyltransferase, catalyzes C-methylation at the C2 position of cytidylylated 2-hydroxyethylphosphonate (HEP-CMP) to afford cytidylylated 2-hydroxypropylphosphonate (HPP-CMP) in fosfomycin biosynthesis. In this study, the Fom3 reaction product HPP-CMP was reanalyzed by chiral ligand exchange chromatography to confirm its stereochemistry. The Fom3 methylation product was found to be ( S)-HPP-CMP only, indicating that the stereochemistry of the C-methylation catalyzed by Fom3 is ( S)-selective.
View Article and Find Full Text PDFOn the stereochemistry of 2-hydroxyethylphosphonate dioxygenase.
J Am Chem Soc
March 2011
Howard Hughes Medical Institute and Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
Stereochemical investigations have shown that the conversion of 2-hydroxyethylphosphonate to hydroxymethylphosphonate by the enzyme HEPD involves removal of the pro-S hydrogen at C2 and, surprisingly, the loss of stereochemical information at C1. As a result, the mechanisms previously proposed for HEPD must be re-evaluated.
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