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

• Main Authors: Zhong, Aoshu (Author), Sun, He G. (Author), Liu, Hung-wen (Author), Rabb, Jennifer (Contributor), Drennan, Catherine L. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Chemistry (Contributor)
• Format: Article
• Language: English
• Published: Springer Nature, 2018-06-15T18:03:53Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institutes of Health (U.S.) (Grant F32-GM108189)