Aminoacyl Sulfonamide Assembly In SB-203208 Biosynthesis

Sulfonamide is present in many important drugs,due to its unique chemical and biological properties.In contrast,naturally occurring sulfonamides are rare,and their biosynthesis has not been investigated.Here we identified the biosynthetic gene cluster of sulfonamide antibiotics,altemicidin(1),SB-203207(2),and SB-203208(3),from Streptomyces sp.NCIMB40513.The heterologous gene expression and biochemical analyses revealed unique aminoacyl transfer reactions,including the tRNA synthetase-like enzyme SbzA-catalyzed L-isoleucine transfer,the GNAT enzyme SbzC-catalyzed β-methylphenylalanine transfer and the second GNAT enzyme Sbzl-catalyzed 2-sulfamoylacetic acid transfer.Furthermore,we elucidated the biogenesis of 2-sulfamoylacetic acid from L-cysteine,by the collaboration of the cupin dioxygenase SbzM and the aldehyde dehydrogenase SbzJ.Remarkably,SbzM catalyzed the two-step oxidation and decarboxylation of L-cysteine,and the subsequent intramolecular amino group rearrangement led to N-S bond formation.This is the first report of the unprecedented biosynthetic machineries of aminoacyl sulfonamide antibiotics,and it paves the way toward investigations of novel amino acid metabolism and their engineered biosynthesis.