Abstract
Sulfonamide is present in many important drugs, due to its unique chemical and biological properties. In contrast, naturally occurring sulfonamides are rare, and their biosynthetic knowledge are scarce. Here we identify the biosynthetic gene cluster of sulfonamide antibiotics, altemicidin, SB-203207, and SB-203208, from Streptomyces sp. NCIMB40513. The heterologous gene expression and biochemical analyses reveal unique aminoacyl transfer reactions, including the tRNA synthetase-like enzyme SbzA-catalyzed L-isoleucine transfer and the GNAT enzyme SbzC-catalyzed β-methylphenylalanine transfer. Furthermore, we elucidate the biogenesis of 2-sulfamoylacetic acid from L-cysteine, by the collaboration of the cupin dioxygenase SbzM and the aldehyde dehydrogenase SbzJ. Remarkably, SbzM catalyzes the two-step oxidation and decarboxylation of L-cysteine, and the subsequent intramolecular amino group rearrangement leads to N-S bond formation. This detailed analysis of the aminoacyl sulfonamide antibiotics biosynthetic machineries paves the way toward investigations of sulfonamide biosynthesis and its engineering.
Highlights
Sulfonamide is present in many important drugs, due to its unique chemical and biological properties
Since the resistance gene for a specific antibiotic is often clustered with its biosynthetic genes, we focused on the Ile-tRNA synthetase genes in the genome
The results demonstrated that SbzA efficiently catalyzes the N-aminoacyl transfer reaction of Lisoleucine onto the primary sulfonamide of 1 to yield 2, in the presence of Ile-tRNAE.coliIle, which was supplied by an in vitro translation kit based on an E. coli lysate (Fig. 3a, d)
Summary
Sulfonamide is present in many important drugs, due to its unique chemical and biological properties. 1234567890():,; Actinomycetical alkaloids exhibit remarkable structural diversity, as represented by peptide, aminobenzoate, oxazole, thiazole, and indolocarbazole-derived secondary metabolites[1,2,3,4,5] Their biosynthetic pathways are rich in rare enzymes, including those that catalyze heteroatom–heteroatom (X–X) bond-forming reactions, thereby appending important biological functions to the molecules[6]. We elucidate the three aminoacyl transfer reactions, including the tRNA synthetase-like enzyme SbzA-catalyzed installation of L-isoleucine onto 1 to afford 2, and the biogenesis of a sulfonamide from L-cysteine by the cupin dioxygenase SbzM. These unusual biosynthetic machineries lead to the construction of the rare aminoacyl sulfonamide molecular scaffold
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