Studies reveal the synthesis mechanism and biological function of cyclosporine

2024-11-09 20:00:38

October 17, 2018 Source: Chinese Academy of Sciences

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On October 2nd, the international academic journal mBio published a research paper entitled "Cyclosporine biosynthesis in Tolypocladium inflatum benefits fungal adaptation to the environment" by the Institute of Plant and Plant Science Excellence Innovation / Institute of Plant Physiology and Ecology, Chinese Academy of Sciences. This work reported the molecular mechanism, regulatory mechanism and biological function of cyclosporine from Cordyceps sinensis.

The general Cordyceps including fungi and fungi can synthesize structurally diverse small molecule compounds, but the synthesis mechanism and biological functions of different compounds are unclear. Wang Chengshu's previous research revealed the synthesis of Metarhizium (destruxins; PNAS, 2012), Beauveria bassiana (Osporein; PNAS, 2015), and Cordyceps sinensis (cordycepin) and pentastatin The molecular mechanism of pentostatin (Cell Chem Biol, 2017), as well as insecticidal or antibacterial activity mediated by different compounds, promotes the chemical biology of broad-based Cordyceps fungi.

Cyclosporine (also known as cyclosporin or cyclosporine) is a non-ribosomal cyclic polypeptide consisting of 11 normal and abnormal amino acids. It was first isolated and identified in 1971, and more than 30 structural similarities were found. Object. Among them, cyclosporine A (CsA) with antifungal activity was approved by the FDA in 1983 as a commercial drug against immune rejection, but the complete mechanism of synthesis of this compound has not been known. Wang Xiuqing, Ph.D. student of Wang Chengshu's research group, carried out a series of gene deletions and intermediates in the gene cluster containing potential non-ribosomal polypeptide synthesis NRPS (SimA) and polyketide synthase PKS (SimG) after analyzing the genome information of M. benthamiana. The separation and identification of the product and the feeding of the substrate were used to analyze the synthesis mechanism of cyclosporine. It is proved that the SimG pathway in the gene cluster is responsible for the synthesis of the non-normal amino acid 2-butenyl-4-methyl-threonine Bmt. The racemase SimB is responsible for converting L-alanine to D-type alanine. SimA mediates sequential addition and cyclization of 11 substrates to generate CsA. The study also revealed that bZIP-type transcription factor SimL regulates gene cluster gene expression and product synthesis, cyclophilin SimC and extracellular transporter SimD are involved in the protection of cytotoxins caused by the synthesis of CsA. Bioassays have shown that the synthesis of CsA can help the bacteria to antagonize other fungi in the environment, and at the same time promote the insecticidal activity of S. sinensis.

This work systematically analyzed the biosynthesis and regulation mechanism of cyclosporine, and further proved that the secondary metabolites synthesized by fungi have important biological functions for producing bacteria.

The study was funded by the National Fund Committee and the Strategic Leadership B of the Chinese Academy of Sciences.

Studies reveal the synthesis mechanism and biological function of cyclosporine

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