Institute of Materia Medica Makes Progress in Studies on Biosynthesis of Endogenous Fungi Natural Product in Toxic Medicinal Plants


Following the discoveries of novel structural compound Penicillactones A-C (Org. Lett., 2013, 15, 5206-5209), mycotoxin Rubratoxin B, and other substances from endophytic fungi Penicillium dangeardii in toxic medicinal plant Lysidice rhodostegia, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines affiliated to the Institute of Materia Medica has made another important progress in research on biosynthesis mechanism.

Recently, Angewandte Chemie International Edition, a top journal in the field of chemistry, made online publication on the latest findings of the State Key Laboratory: multi-step tandem redox reactions involve in biosynthesis of protein phosphatase inhibitor Rubratoxin A. According to the authors, dimer acid anhydride precursor can produce mycotoxin Rubrotoxin B through selective oxidization of four α-ketoglutarate (α-KG)-dependent dioxygenases and oxidation of a flavin adenine dinucleotide (FAD)-binding protein,. Ultimately, under the impact of a ferric reductase, carbonyl of one of the maleic anhydrides is selectively reduced to form γ-hydroxy butenolide, resulting in a potential antitumor drug Rubrotoxin A. Meanwhile, RbtB, one of the α-KG oxidases, rarely involves in the two-step oxidation in different positions and at different biosynthesis stages. For the first time ferric reductases were found to be involve in the biosynthesis of natural products. While ferric reductases usually involve in Fe2+ absorption into plants and microorganisms or electron transfer of respiratory chain, this new discovery was achieved on biosynthesis of natural products.



                                                                                                                                (Mycotoxin)                               (PP2A Inheritor)

This new discovery reveals how endophytic fungus, which acts as a “drug factory”, synthesizes highly toxic mycotoxins through the complicate oxidase system, utilizes the reductase system to modify toxophore, alleviates toxicity of  toxophore and improves anti-cancer activity of toxophore. This vividly demonstrates the whole process that the nature magically gives birth to a “demon” and helps such a “demon” transform into an “angel”.

Multidisciplinary research teams, led by Research Fellow Youcai Hu, Research Fellow Shishan Yu, and Visiting Research Fellow Yi Tang, respectively, jointly completed this study. The research team led by Youcai Hu specializes in the discovery of fungal natural products and studies on biosynthesis; research team led by Shishan Yu specializes in toxic medicinal plants and active natural products of their endogenous fungi; and research team led by Yi Tang specializes in natural drug synthesis biology. These three research teams exert concerted efforts to establish an integrated research system of toxic medicinal plant-endophytic fungi-mycotoxin- biosynthesis, which emerges as the new growth engine for the State Key Laboratory to carry forward the legacies, develop by leaps and bounds, and launch collaborative research projects. This was also Dr. Youcai Hu’s second article published on Angewandte Chemie International Edition as Corresponding Author since he began to work in the Institute of Materia Medica.

On the occasion of the upcoming centurial anniversary of PUMC, the State Key Laboratory celebrates this grand event and pays a tribute to PUMC with this research finding.


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Contributed by: National-class Key Laboratory of Natural Materia Medica Active Substances and Functions affiliated to the Institute of Materia Medica