New Insights into the Biosynthesis of Fosfazinomycin.

The biosynthetic origin of a unique hydrazide moiety in the phosphonate natural product fosfazinomycin is unknown. This study presents the activities of five proteins encoded in its gene cluster. The flavin dependent oxygenase FzmM catalyses the oxidation of L-Asp to -hydroxy-Asp. When FzmL is added, fumarate is produced in addition to nitrous acid. The adenylosuccinate lyase homolog FzmR eliminates acetylhydrazine from -acetylhydrazinosuccinate, which in turn is the product of FzmQ-catalysed acetylation of hydrazinosuccinate. Collectively, these findings suggest a path to -acetylhydrazine from L-Asp. The incorporation of nitrogen from L-Asp into fosfazinomycin was confirmed by isotope labelling studies. Installation of the N-terminal Val of fosfazinomycin is catalysed by FzmI in a Val-tRNA dependent process.