Mechanism of Post-Translational Peptide Modification in Microcin B17 Synthetase

• Applicant: Professor Dr. Florian Hollfelder
• Subject Area: Biochemistry
• Term: from 1999 to 2002
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5209814

Post-translational modification turns simple peptides into complex natural products with a wide range of unique pharmacological activities. The bacterial antibiotic microcin B17 (a putative DNA gyrase inhibitor) is an example for a general strategy employed by nature to confer antibiotic or other activities: Cysteine and serine side chains are converted to oxazole and thiazole heterocycles, i.e. modifications that alter the architecture of the natural product dramatically. Such structural elements are germane to many pharmacologically active peptide-based compounds, such as bleomycin A5 (anti-tumor), thiangazole (anti-HIV) hennoxazole A.(anti-viral) and many more of therapeutic interest. How does the bacterial enzyme machinery bring about the transformation at issue? In this project the mechanism of one of the enzymes involved in microcin B17 biosynthesis, the flavin mononucleotide-containing McbC, the putative dehydrogenase in the oxazole/thiazole formation, will be probed. The envisaged mechanistic framework will provide a knowledge base for combinatorial biosynthesis by rational design of module assembly and module engineering.

• DFG Programme: Emmy Noether International Fellowships