Understanding the biosynthesis of the glycopeptide antibiotics
Department of Biochemistry & Molecular Biology, Monash University, Clayton, VIC 3800.
The glycopeptide antibiotics (GPAs) are a structurally complex and medically important class of peptide natural products that include the clinical antibiotics vancomycin and teicoplanin. They contain a large number of non-proteinogenic amino acids and are produced by a linear non-ribosomal peptide synthetase (NRPS) machinery comprising seven modules. Furthermore, GPAs are extensively crosslinked late in their biosynthesis on the NRPS assembly line by the actions of a cascade of Cytochrome P450 enzymes, a process which contributes to the rigidity and structural complexity of these compounds. Due to the challenge of synthesising GPAs, biosynthesis remains the only means of accessing GPAs for clinical use, which makes understanding the biosynthesis of GPAs of key importance. Here I will detail results from our studies into the NRPS machinery, the P450-cyclisation cascade and the interplay of these two important processes during GPA biosynthesis. These demonstrate how selectivity is mediated through the careful orchestration of critical modification steps and interactions between the peptide-producing NRPS machinery and trans-modifying enzymes.