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Biological Chemistry

Megaenzyme Mechanisms Revealed

Structural Biochemistry: Nonribosomal peptide synthetase crystal structures reveal biosynthetic secrets

by Stu Borman
January 18, 2016 | APPEARED IN VOLUME 94, ISSUE 3

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Credit: Nature
New structural data reveal how a peptidyl carrier protein (PCP) makes a 75° swing and moves 61 Å as it transitions between thiol and formyl states in an antibiotic-producing NRPS.
Credit: Nature
New structural data reveal how a peptidyl carrier protein (PCP) makes a 75° swing and moves 61 Å as it transitions between thiol and formyl states in an antibiotic-producing NRPS.

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.

VISUALIZING MECHANISMS
Martin Schmeing discusses the rationale for his group’s new structural study on an antibiotic-producing NRPS and shows simulations of the megaenzyme’s inner workings.
Credit: McGill University Services
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