New Role for Radical SAM Enzymes in the Biosynthesis of Thio(seleno)oxazole RiPP Natural Products

Lewis, Julia K.; Jochimsen, Andrew S.; Lefave, Sarah J.; Young, Anthony P.; Kincannon, William M.; Roberts, Andrew G.; Kieber-Emmons, Matthew T.; Bandarian, Vahe

doi:10.1021/acs.biochem.1c00469

Title: New Role for Radical SAM Enzymes in the Biosynthesis of Thio(seleno)oxazole RiPP Natural Products

Journal Article · 03 November 2021 · Biochemistry

DOI: https://doi.org/10.1021/acs.biochem.1c00469 · OSTI ID:1828807

Lewis, Julia K. ^[1]; Jochimsen, Andrew S. ^[1]; Lefave, Sarah J. ^[1];

^[1]; Kincannon, William M. ^[1]; Roberts, Andrew G. ^[1];

^[1];

^[1]

Univ. of Utah, Salt Lake City, UT (United States)

Ribosomally synthesized post-translationally modified peptides (RiPPs) are ubiquitous and represent a structurally diverse class of natural products. The ribosomally encoded precursor polypeptides are often extensively modified posttranslationally by enzymes that are encoded by coclustered genes. Radical S-adenosyl-L-methionine (SAM) enzymes catalyze numerous chemically challenging transformations. In RiPP biosynthetic pathways, these transformations include the formation of C-H, C-C, C-S, and C-O linkages. Here in this paper, we show that the Geobacter lovleyi sbtM gene encodes a radical SAM protein, SbtM, which catalyzes the cyclization of a Cys/SeCys residue in a minimal peptide substrate. Biochemical studies of this transformation support a mechanism involving H-atom abstraction at the C-3 of the substrate Cys to initiate the chemistry. Several possible cyclization products were considered. The collective biochemical, spectroscopic, mass spectral, and computational observations point to a thiooxazole as the product of the SbtM-catalyzed modification. To our knowledge, this is the first example of a radical SAM enzyme that catalyzes a transformation involving a SeCys-containing peptide and represents a new paradigm for formation of oxazole-containing RiPP natural products.

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Research Organization:: Univ. of Utah, Salt Lake City, UT (United States)

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

Grant/Contract Number:: SC0020954

OSTI ID:: 1828807

Alternate ID(s):: OSTI ID: 1831411

Journal Information:: Biochemistry, Vol. 60, Issue 45; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Title: New Role for Radical SAM Enzymes in the Biosynthesis of Thio(seleno)oxazole RiPP Natural Products

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