A B12-dependent radical SAM enzyme involved in oxetanocin A biosynthesis

Jennifer Bridwell-Rabb, Aoshu Zhong, He G. Sun, Catherine L. Drennan () and Hung-wen Liu ()
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Jennifer Bridwell-Rabb: Howard Hughes Medical Institute, Massachusetts Institute of Technology
Aoshu Zhong: College of Pharmacy, University of Texas
He G. Sun: College of Pharmacy, University of Texas
Catherine L. Drennan: Howard Hughes Medical Institute, Massachusetts Institute of Technology
Hung-wen Liu: College of Pharmacy, University of Texas

Nature, 2017, vol. 544, issue 7650, 322-326

Abstract: Abstract Oxetanocin A (OXT-A) is a potent antitumour, antiviral and antibacterial compound. Biosynthesis of OXT-A has been linked to a plasmid-borne Bacillus megaterium gene cluster that contains four genes: oxsA, oxsB, oxrA and oxrB. Here we show that both the oxsA and oxsB genes are required for the production of OXT-A. Biochemical analysis of the encoded proteins, a cobalamin (Cbl)-dependent S-adenosylmethionine (AdoMet) radical enzyme, OxsB, and an HD-domain phosphohydrolase, OxsA, reveals that OXT-A is derived from a 2′-deoxyadenosine phosphate in an OxsB-catalysed ring contraction reaction initiated by hydrogen atom abstraction from C2′. Hence, OxsB represents the first biochemically characterized non-methylating Cbl-dependent AdoMet radical enzyme. X-ray analysis of OxsB reveals the fold of a Cbl-dependent AdoMet radical enzyme, a family of enzymes with an estimated 7,000 members. Overall, this work provides a framework for understanding the interplay of AdoMet and Cbl cofactors and expands the catalytic repertoire of Cbl-dependent AdoMet radical enzymes.

Date: 2017
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DOI: 10.1038/nature21689

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