聚酮
非核糖体肽
聚酮合酶
DNA
生物化学
生物
生物合成
链霉菌
化学
基因
遗传学
细菌
作者
Qiuyue Nie,Shiqi Fang,Lian Wu,Ruo‐Qin Gao,Yu Hu,Dian Ding,Hai‐Xue Pan,Zeng‐Fei Pei,Jun‐Bin He,Qiang Zhou,Zihui Chen,Xianfeng Hou,Xin‐Qing Zhao,Gong‐Li Tang
出处
期刊:Angewandte Chemie
[Wiley]
日期:2025-08-05
卷期号:64 (39): e202512820-e202512820
被引量:4
标识
DOI:10.1002/anie.202512820
摘要
DNA alkylating natural products usually exhibit diverse bioactivity and serve as a crucial source of drug leads. Here, we employed genome mining guided by HTH-42 superfamily resistance gene to precisely discover a new class of DNA-alkylating antibiotics, xinghaicarcins, from Streptomyces xinghaiensis. They possess an intricate spiro-epoxide-bearing spiroketal heptacyclic scaffold fused with a pipecolic acid, assembled by a type II polyketide synthase-nonribosomal peptide synthetase hybrid system. An aminotransferase XhnB1 and a methyltransferase XhnM are identified to catalyze the formation of N-methylated pipecolic acid building block, leading to the completion of the polyketide-peptide backbone. The identification of XhnM facilitated stereochemical determination of six chiral centers in xinghaicarcins by co-crystallization. Notably, xinghaicarcins exhibit potent antibacterial activity against drug-resistant pathogens and cytotoxicity against multiple cancer cell lines. Additionally, the HTH-42 superfamily resistant protein, XhnU2, was characterized to mitigate xinghaicarcin-induced genotoxicity. This work provides comprehensive insights into structure, biosynthesis, bioactivity, and self-resistance mechanisms of xinghaicarcins, expanding diversity of DNA alkylating natural products.
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