Thiazolyl Peptide Antibiotic Biosynthesis: A Cascade of Post-translational Modifications on Ribosomal Nascent Proteins

摘要: Antibiotics of the thiocillin, GE2270A, and thiostrepton class, which block steps in bacterial protein synthesis, contain a trithiazolyl (tetrahydro)pyridine core that provides architectural constraints for high affinity binding to either 50 S ribosomal subunit or elongation factor Tu. These mature antibiotic scaffolds arise from cascade post-translational modifications on 50–60-residue prepeptide precursors trim away N-terminal leader sequences (∼40 residues) while C-terminal 14–18 residues are converted into scaffold. In producing microbes, genes encoding open reading frames flanked biosynthetic clusters by modification enzymes carry out lantibiotic-type dehydrations Ser Thr dehydroamino acid side chains, cyclodehydration oxidation cysteines thiazoles, condensation two dehydroalanine en route core. The pyridine framework thus arises peptide backbone three Cys prepeptide.