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    Home > Zhu dunming and Wu Qiqing, researchers of Tianjin Institute of technology, Chinese Academy of Sciences, have made new progress in the transformation of carbonyl reductase and the precise construction of complex molecules with multiple chiral centers

    Zhu dunming and Wu Qiqing, researchers of Tianjin Institute of technology, Chinese Academy of Sciences, have made new progress in the transformation of carbonyl reductase and the precise construction of complex molecules with multiple chiral centers

    • Last Update: 2019-10-28
    • Source: Internet
    • Author: User
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    Important drug molecules and natural products usually contain multiple chiral centers, and the configuration of these chiral centers has a decisive influence on their biological activities One of the most challenging fields in organic synthesis chemistry is how to construct multiple chiral centers in complex molecules with high efficiency and high stereoselectivity Levonorgestrel (levonorgestrel) and gestodene (gestodene) are two very important small-molecule contraceptives In 2018, the global retail drugs ranked in the top 200, with a total sales volume of 2 billion US dollars (13R, 17s) - Ethel secol is the key intermediate for the synthesis of these two drugs One method for the direct preparation of (13R, 17s) - Ethel secol is the desymmetric reduction of Ethel secodine, because there are two identical carbonyls in Ethel secodine molecule that can be reduced, and one quaternary carbon atom, possibly 10 configuration products From 1960s till now, the scientific community has not solved the problems of poor stereoselectivity, low conversion efficiency and complex products in the synthesis process The team of biocatalysis and green chemical industry led by Zhu dunming and Wu Qiqing of Tianjin Institute of industrial biotechnology, Chinese Academy of Sciences, first screened 100 kinds of carbonyl reductase in the laboratory, analyzed and compared the conversion results, which have been originated from Ralstonia since Through several rounds of modification and selection, the mutant rasadh F12, which can efficiently catalyze the substrate Ethel secodine, was obtained The activity of the mutant rasadh F12 to the substrate increased 183 times, the ratio of the target product increased from 37.3% to > 99.5%, and the ratio of the bicarbonyl reduction product decreased from 18.8% to < 0.1% And the conversion of kilogram level substrate was realized, which laid a foundation for industrial application The obtained mutant enzyme has a good substrate spectrum and can be applied to the asymmetric reduction of 2,2-disubstituted-1,3-cyclopentadienone with various structures to obtain a single configuration product The research team further cooperated with Liu Weidong, an associate researcher, and professor s í Lvia Osuna from Spain, through the crystal structure analysis and molecular dynamics calculation of the mutant enzyme and the product complex The molecular mechanism of improving the catalytic activity and stereoselectivity of the mutant enzyme was analyzed, which provided a theoretical basis for the further design and transformation of carbonyl reductase to achieve the precise construction of multi chiral complex molecules The research work has been supported by the national key research and development plan, the key project of synthetic biology, the National Natural Science Foundation and the platform project of Tianjin Science and Technology Bureau Relevant research results were published in nature Catalysis (DOI: 10.1038 / s41929-019-0347-y) Chen Xi, the research team's associate researcher, and Zhang hongduri, the research assistant, were the first authors of the paper Zhu dunming, Wu Qiqing, researcher of Tianjin Institute of industrial biology, Chinese Academy of Sciences, and professor s í Lvia Osuna from Spain are the corresponding authors.
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