Megaenzyme Mechanisms Revealed

A pair of structural studies have revealed key operations of nonribosomal peptide synthetases (NRPSs), which are megaenzymes that bacteria and fungi use to produce peptide natural products, including drugs such as vancomycin and cyclosporine. Scientists would like to know more about how these assembly-line biosynthetic systems work so they can better engineer them to produce customized natural products as potential therapeutics. But NRPS structures are scarce and difficult to obtain. Now, crystal structures of an antibiotic-producing NRPS module by T. Martin Schmeing and coworkers at McGill University reveal a dramatic 75° rotation and 61-Å motion of a peptidyl carrier protein as it moves between catalytic sites that thiolate and then formylate a biosynthetic intermediate (Nature 2016, DOI: 10.1038/nature16503). And Andrew M. Gulick of Hauptman-Woodward Medical Research Institute and the University at Buffalo, SUNY, and coworkers have obtained NRPS crystal structures that show how condensation and adenylation sites adopt catalytic conformations simultaneously, boosting biosynthetic efficiency (Nature 2016, DOI: 10.1038/nature16163). To ease rational engineering of NRPSs to make novel bioactive natural products, more studies like these will be needed, comments Michael D. Burkart of the University of California, San Diego.