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A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the Protein Phosphatase‐2 Inhibitor Rubratoxin A
Author(s) -
Bai Jian,
Yan Daojiang,
Zhang Tao,
Guo Yongzhi,
Liu Yunbao,
Zou Yi,
Tang Mancheng,
Liu Bingyu,
Wu Qiong,
Yu Shishan,
Tang Yi,
Hu Youcai
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201701547
Subject(s) - redox , ferredoxin , flavin group , chemistry , enzyme , cofactor , dehydrogenase , biosynthesis , reductase , biochemistry , coenzyme a , stereochemistry , combinatorial chemistry , organic chemistry
Redox modifications are key complexity‐generating steps in the biosynthesis of natural products. The unique structure of rubratoxin A ( 1 ), many of which arise through redox modifications, make it a nanomolar inhibitor of protein phosphatase 2A (PP2A). We identified the biosynthetic pathway of 1 and completely mapped the enzymatic sequence of redox reactions starting from the nonadride 5 . Six redox enzymes are involved, including four α‐ketoglutarate‐ and iron(II)‐dependent dioxygenases that hydroxylate four sp 3 carbons; one flavin‐dependent dehydrogenase that is involved in formation of the unsaturated lactone; and the ferric‐reductase‐like enzyme RbtH, which regioselectively reduces one of the maleic anhydride moieties in rubratoxin B to the γ‐hydroxybutenolide that is critical for PP2A inhibition. RbtH is proposed to perform sequential single‐electron reductions of the maleic anhydride using electrons derived from NADH and transferred through a ferredoxin and ferredoxin reductase pair.