A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the Protein Phosphatase‐2 Inhibitor Rubratoxin A

• Published in: Angewandte Chemie International Edition Vol. 56; no. 17; pp. 4782 - 4786
• Main Authors: Bai, Jian, Yan, Daojiang, Zhang, Tao, Guo, Yongzhi, Liu, Yunbao, Zou, Yi, Tang, Mancheng, Liu, Bingyu, Wu, Qiong, Yu, Shishan, Tang, Yi, Hu, Youcai
• Format: Journal Article
• Language: English
• Published: Germany 18-04-2017
• Subjects: biosynthesis; Biosynthetic Pathways; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Multigene Family; Mycotoxins - chemistry; Mycotoxins - metabolism; Mycotoxins - pharmacology; natural products; nonadrides; Penicillium - enzymology; Penicillium - genetics; Penicillium - metabolism; Protein Phosphatase 2 - antagonists & inhibitors; redox enzymes; rubratoxins; natural products; rubratoxins; redox enzymes; biosynthesis; nonadrides
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201701547

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 sp3 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.
Hit for six: Four α‐ketoglutarate‐dependent dioxygenases (red) that hydroxylate sp3 carbon atoms, a flavin‐dependent dehydrogenase (blue) that forms the unsaturated lactone, and the highly unusual ferric‐reductase‐like enzyme RbtH (green) are involved in the biosynthesis of rubratoxin A. RbtH regioselectively reduces one of the maleic anhydride moieties in the intermediate rubratoxin B to the γ‐hydroxybutenolide group that is critical for the biological activity.