title: A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the Protein Phosphatase-2 Inhibitor Rubratoxin A.
abstract: 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 sp3carbons; 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.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Daojiang
authors.initials: D
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Yunbao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Chemical and Biomolecular Engineering, Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Mancheng
authors.initials: M
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Bingyu
authors.initials: B
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Shishan
authors.initials: S
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.|Department of Chemical and Biomolecular Engineering, Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Hu
mesh_terms: D053898:Biosynthetic Pathways; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005810:Multigene Family; D009183:Mycotoxins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010407:Penicillium / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D009183:Mycotoxins; C100297:rubratoxins; D054648:Protein Phosphatase 2
keywords: biosynthesis; natural products; nonadrides; redox enzymes; rubratoxins