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Characterization of the cobalamin-dependent radical S-adenosyl-l-methionine enzyme C-methyltransferase Fom3 in fosfomycin biosynthesis. | LitMetric

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., but biosynthesis of fosfomycin significantly differs between the two bacteria, especially in the incorporation mechanism of the methyl group. It has been proposed that the cobalamin-dependent radical S-adenosyl-l-methionine (SAM) enzyme Fom3 is responsible for the methyl-transfer reaction in Streptomyces fosfomycin biosynthesis. In this chapter, we describe the experimental methods to characterize Fom3. We performed the methylation reaction with the purified recombinant Fom3, revealing that Fom3 recognizes a cytidylylated 2-hydroxyethylphosphonate as a substrate and catalyzes stereoselective methylation of the sp carbon at the C2 position to afford cytidylylated (S)-2-hydroxypropylphosphonate. Reaction analysis using deuterium-labeled substrates showed that the 5'-deoxyadenosyl radical generated by reductive cleavage of SAM stereoselectively abstracts the pro-R hydrogen atom of the CH bond at the C2 position of cytidylylated 2-hydroxyethylphosphonate. Therefore, the C-methylation reaction catalyzed by Fom3 proceeds with inversion of the configuration at the C2 position. Experimental methods to elucidate the chemical structures of the substrate and products and the stereochemical course in the Fom3-catalyzed reaction could give information to progress investigation of cobalamin-dependent radical SAM C-methyltransferases.

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http://dx.doi.org/10.1016/bs.mie.2021.11.025DOI Listing

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