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Structural diversification of bioactive bibenzyls through modular co-culture leading to the discovery of a novel neuroprotective agent

查看全文 作　　者：Yuyu [1]Liu;Xinnan [1]Li;Songyang [1]Sui;Jingshu [1]Tang;Dawei [1]Chen;Yuying [1]Kang;Kebo [1]Xie;Jimei [1]Liu;Jiaqi [1]Lan;Lei [1]Wu;Ridao [1]Chen;Ying [1]Peng;Jungui [1]Dai 高影响力作者 机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs,and NHC Key Laboratory of Biosynthesis of Natural Products,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China高影响力机构 出　　处：《Acta Pharmaceutica Sinica B》索引2023年第13卷第4期,共15页高影响力期刊 基　　金：supported by the National Key Research and Development Program of China(2020YFA0908000);CAMS Innovation fund for Medical Sciences(CIFMS-2021-I2M1-028 and CIFMS-2021-I2M-1-029,China);Beijing Key Laboratory of non-Clinical Drug Metabolism and PK/PD Study(Z141102004414062,China)。 摘　　要：Bibenzyls,a kind of important plant polyphenols,have attracted growing attention for their broad and remarkable pharmacological activities.However,due to the low abundance in nature,uncontrollable and environmentally unfriendly chemical synthesis processes,these compounds are not readily accessible.Herein,one high-yield bibenzyl backbone-producing Escherichia coli strain was constructed by using a highly active and substrate-promiscuous bibenzyl synthase identified from Dendrobium officinale in combination with starter and extender biosynthetic enzymes.Three types of efficiently postmodifying modular strains were engineered by employing methyltransferases,prenyltransferase,and glycosyltransferase with high activity and substrate tolerance together with their corresponding donor biosynthetic modules.Structurally different bibenzyl derivatives were tandemly and/or divergently synthesized by co-culture engineering in various combination modes.Especially,a prenylated bibenzyl derivative(12)was found to be an antioxidant that exhibited potent neuroprotective activity in the cellular and rat models of ischemia stroke.RNA-seq,quantitative RT-PCR,and Western-blot analysis demonstrated that 12 could up-regulate the expression level of an apoptosis-inducing factor,mitochondria associated 3(Aifm3),suggesting that Aifm3 might be a new target in ischemic stroke therapy.This study provides a flexible plug-and-play strategy for the easy-to-implement synthesis of structurally diverse bibenzyls through a modular co-culture engineering pipeline for drug discovery. 关 键 词：BIBENZYLS Modular co-culture engineering Promiscuous enzymes Neuroprotective agent Aifm3 Dendrobium officinale
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