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The Biosynthetic Mechanism of Protein Phosphatase-2 Inhibitor Rubratoxin A was Elucidated

Time:2017/4/5 Source:State Key Laboratory of Bioactive Substance and Function of Natural Medicines Read:1788

 

Following the identification of penicillactones A–C and rubratoxin B in the endophytic fungus Penicillium dangeardii from toxic medicinal plant Lysidice rhodostegia (Org. Lett., 2013, 15, 5206–5209), a significant progress was achieved on the biosynthesis of rubratoxins by researchers from the State Key Laboratory of Bioactive Substance and Function of Natural Medicines in Institute of Materia Medica Chinese Acadey of Medical Science and Peking Union Medical College.

 Recently, a paper titled “A Cascade of Redox Reactions Generates Complexity in the Biosynthesis of the Protein Phosphatase-2 Inhibitor Rubratoxin A” was published online at Angewandte Chemie International Edition.  In this study, researchers from the State Key Laboratory of Bioactive Substance and Function of Natural Medicines identified the biosynthetic pathway of rubratoxin A and completely mapped the enzymatic sequence of redox reactions starting from a simple nonadride. Six redox enzymes are involved, including four -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 a ferric-reductase like enzyme RbtH which regioselectively reduces one of the maleic anhydride moieties in rubratoxin B into the -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. The results show that how the fungus "drug factory" utilized the complex oxidase system to convert a simple inactive maleic anhydride dimer to a structurally complex mycotoxin “Devil” and further to a promising antitumor agent, the “Angel” by the reductase system, demonstrating the amazing of Nature.

This research was accomplished under the cooperation of Prof. Youcai Hu, Prof. Shishan Yu and Prof. Yi Tang from the State Key Laboratory of Bioactive Substance and Function of Natural Medicines. Prof. Hu’s lab is focusing on the discovery and biosynthesis of fungal natural products, Prof. Yu’s lab is working on the bioactive natural products from toxic medicinal plants and endophytic fungus, while Prof. Tang’s group is specializing in the synthetic biology of natural medicine.

This paper is dedicated to the 100th anniversary of Peking Union Medical College

The article is available online.

 

 

 

 

 

 

 

 

 

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