Structures and function of a tailoring oxidase in complex with a nonribosomal peptide synthetase module

Fortinez, Camille Marie; Bloudoff, Kristjan; Harrigan, Connor; Sharon, Itai; Strauss, Mike; Schmeing, T. Martin

doi:10.1038/s41467-022-28221-y

Title: Structures and function of a tailoring oxidase in complex with a nonribosomal peptide synthetase module

Journal Article · Thu Jan 27 00:00:00 EST 2022 · Nature Communications

DOI:https://doi.org/10.1038/s41467-022-28221-y· OSTI ID:1847676

Fortinez, Camille Marie ^[1]; Bloudoff, Kristjan ^[1]; Harrigan, Connor ^[1];

^[1];

^[1]

McGill Univ., Montreal, QC (Canada)

Nonribosomal peptide synthetases (NRPSs) are large modular enzymes that synthesize secondary metabolites and natural product therapeutics. Most NRPS biosynthetic pathways include an NRPS and additional proteins that introduce chemical modifications before, during or after assembly-line synthesis. The bacillamide biosynthetic pathway is a common, three-protein system, with a decarboxylase that prepares an NRPS substrate, an NRPS, and an oxidase. Here, the pathway is reconstituted in vitro. The oxidase is shown to perform dehydrogenation of the thiazoline in the peptide intermediate while it is covalently attached to the NRPS, as the penultimate step in bacillamide D synthesis. Structural analysis of the oxidase reveals a dimeric, two-lobed architecture with a remnant RiPP recognition element and a dramatic wrapping loop. The oxidase forms a stable complex with the NRPS and dimerizes it. We visualized co-complexes of the oxidase bound to the elongation module of the NRPS using X-ray crystallography and cryo-EM. The three active sites (for adenylation, condensation/cyclization, and oxidation) form an elegant arc to facilitate substrate delivery. The structures enabled a proof-of-principle bioengineering experiment in which the BmdC oxidase domain is embedded into the NRPS.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; S10OD021527

OSTI ID:: 1847676

Journal Information:: Nature Communications, Vol. 13, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Structural Characterization of OxyD, a Cytochrome P450 Involved in β-Hydroxytyrosine Formation in Vancomycin Biosynthesis Cryle, Max J.; Meinhart, Anton; Schlichting, Ilme Journal of Biological Chemistry, Vol. 285, Issue 32 https://doi.org/10.1074/jbc.M110.131904	journal	August 2010
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Distinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection Schrettl, Markus; Bignell, Elaine; Kragl, Claudia PLoS Pathogens, Vol. 3, Issue 9 https://doi.org/10.1371/journal.ppat.0030128	journal	September 2007
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