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Gene-Directed Generation of Unprecedented Bioactive Compounds

文献类型： 外文期刊

作者： Lin, Li Ping 1 ; Yu, Hai Ying 1 ; Shi, Jing 2 ; Zhou, Zhen-Zhen 2 ; Tan, Ren Xiang 1 ;

作者机构： 1.Nanjing Univ Chinese Med, State Key Lab Cultivat Base TCM Qual & Efficacy, Nanjing 210023, Jiangsu, Peoples R China

2.Nanjing Univ, Inst Funct Biomol, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China

3.Jiangsu Acad Agr Sci, Prov Key Lab Agrobiol, Nanjing 210014, Jiangsu, Peoples R China

关键词： Daldinia eschscholzii; heterologous PKS assembly lines; indole-3-carbinol; polyketide-indole; Michael addition

期刊名称：ACS SUSTAINABLE CHEMISTRY & ENGINEERING （ 影响因子：8.4； 五年影响因子：8.7 ）

ISSN： 2168-0485

年卷期： 2023 年 11 卷 17 期

页码：

收录情况： SCI

摘要： frameworks are highly desired for the discovery and development of new drugs and agrochemicals, but very few attempts have been reported to generate such molecules in biological contexts. Here, we present a gene-directed generation of architecturally unprecedented polyketide- indole hybrids (PIHs), which was conceptualized and materialized by employing polyketide synthases expressed in a heterologous vector, with simultaneous exposure to exogenous chemicals. To make an exemplification to this generally applicable approach, the ChrA and ChrB genes of Daldinia eschscholzii IFB-TL01 were integrated into the Aspergillus oryzae (AO) cell, and the resultant ChrA/ChrB-AO transformant was cultured in the indole-3-carbinol (I3C)-supplemented medium, leading to the production of seven skeletally undescribed PIHs named aochrabines A-G. Among them, aochrabines A-C exhibited a broad spectrum in inhibiting the growth of Gram-positive bacteria, whereas aochrabines B, C, and G showed moderate antitumor activities. Unexpectedly, the construction of such aochrabine molecules was achieved by the regioselective Michael addition of 3methyleneindolium (3MI, generated from I3C in the AO culture) to different polyketide precursors with the yields (much) higher than those in the D. eschscholzii culture where comparable. Chemically, the benzyl-methine carbons in the precursor molecules were found to be made more vulnerable to the 3MI attack by the hydrogen-bonding between the ortho-hydroxyl and meta-carbonyl groups. Collectively, this is the first report of the ortho- and meta-substituent co-driven regioselective Michael addition of electrophilic methylene compounds to heterologous PKS production platform to in situ multiply the chemodiversity of microbial cultures, thus showing great potential in producing valuable compounds with new chemical space.

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