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Mechanistic Probes for the Epimerization Domain of Nonribosomal Peptide Synthetases |
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| Authors: | Woojoo E. Kim Dr. Ashay Patel Dr. Gene H. Hur Dr. Peter Tufar Dr. Michael G. Wuo Prof. Dr. J. Andrew McCammon Prof. Dr. Michael D. Burkart |
| Affiliation: | 1. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0358 USA These authors contributed equally to this work.;2. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0358 USA Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0636 USA These authors contributed equally to this work.;3. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0358 USA;4. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0358 USA Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0636 USA |
| Abstract: | Nonribosomal peptide synthetases (NRPSs) are responsible for the synthesis of a variety of bioactive natural products with clinical and economic significance. Interestingly, these large multimodular enzyme machineries incorporate nonproteinogenic d -amino acids through the use of auxiliary epimerization domains, converting l -amino acids into d -amino acids that impart into the resulting natural products unique bioactivity and resistance to proteases. Due to the large and complex nature of NRPSs, several questions remain unanswered about the mechanism of the catalytic domain reactions. We have investigated the use of mechanism-based crosslinkers to probe the mechanism of an epimerization domain in gramicidin S biosynthesis. In addition, MD simulations were performed, showcasing the possible roles of catalytic residues within the epimerization domain. |
| Keywords: | enzyme inhibitors epimerization molecular dynamic simulations natural product biosynthesis nonribosomal peptide synthetase (NRPS) |