PMID- 28370936
OWN - NLM
STAT- MEDLINE
DCOM- 20190115
LR  - 20190115
IS  - 1521-3773 (Electronic)
IS  - 1433-7851 (Linking)
VI  - 56
IP  - 17
DP  - 2017 Apr 18
TI  - A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the 
      Protein Phosphatase-2 Inhibitor Rubratoxin A.
PG  - 4782-4786
LID - 10.1002/anie.201701547 [doi]
AB  - 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 alpha-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 
      gamma-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.
CI  - (c) 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
FAU - Bai, Jian
AU  - Bai J
AD  - 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.
FAU - Yan, Daojiang
AU  - Yan D
AD  - 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.
FAU - Zhang, Tao
AU  - Zhang T
AD  - 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.
FAU - Guo, Yongzhi
AU  - Guo Y
AD  - 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.
FAU - Liu, Yunbao
AU  - Liu Y
AD  - 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.
FAU - Zou, Yi
AU  - Zou Y
AD  - 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.
FAU - Tang, Mancheng
AU  - Tang M
AD  - Department of Chemical and Biomolecular Engineering, Department of Chemistry and 
      Biochemistry, University of California, Los Angeles, CA, 90095, USA.
FAU - Liu, Bingyu
AU  - Liu B
AD  - 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.
FAU - Wu, Qiong
AU  - Wu Q
AD  - 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.
FAU - Yu, Shishan
AU  - Yu S
AD  - 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.
FAU - Tang, Yi
AU  - Tang Y
AD  - 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.
AD  - Department of Chemical and Biomolecular Engineering, Department of Chemistry and 
      Biochemistry, University of California, Los Angeles, CA, 90095, USA.
FAU - Hu, Youcai
AU  - Hu Y
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170328
PL  - Germany
TA  - Angew Chem Int Ed Engl
JT  - Angewandte Chemie (International ed. in English)
JID - 0370543
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Mycotoxins)
RN  - 0 (rubratoxins)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - *Biosynthetic Pathways
MH  - Enzyme Inhibitors/chemistry/*metabolism/pharmacology
MH  - Multigene Family
MH  - Mycotoxins/chemistry/*metabolism/pharmacology
MH  - Penicillium/*enzymology/genetics/metabolism
MH  - Protein Phosphatase 2/*antagonists & inhibitors
OTO - NOTNLM
OT  - biosynthesis
OT  - natural products
OT  - nonadrides
OT  - redox enzymes
OT  - rubratoxins
EDAT- 2017/04/04 06:00
MHDA- 2019/01/16 06:00
CRDT- 2017/04/04 06:00
PHST- 2017/02/13 00:00 [received]
PHST- 2017/04/04 06:00 [pubmed]
PHST- 2019/01/16 06:00 [medline]
PHST- 2017/04/04 06:00 [entrez]
AID - 10.1002/anie.201701547 [doi]
PST - ppublish
SO  - Angew Chem Int Ed Engl. 2017 Apr 18;56(17):4782-4786. doi: 
      10.1002/anie.201701547. Epub 2017 Mar 28.