羟基化
非核糖体肽
化学
活动站点
酶
生物化学
区域选择性
聚酮合酶
立体化学
黄蛋白
生物合成
聚酮
催化作用
作者
Zhiyin Yu,Jianping Huang,Jing Yang,Chongxi Liu,Yijun Yan,Li Wang,Junwei Zhao,Yin Chen,Wensheng Xiang,Sheng-Xiong Huang
标识
DOI:10.1038/s41467-023-35829-1
摘要
Abstract Angiotensin-converting enzyme inhibitors are widely used for treatment of hypertension and related diseases. Here, six karnamicins E 1 -E 6 ( 1 – 6 ), which bear fully substituted hydroxypyridine and thiazole moieties are characterized from the rare actinobacterium Lechevalieria rhizosphaerae NEAU-A2. Through a combination of isotopic labeling, genome mining, and enzymatic characterization studies, the programmed assembly of the fully substituted hydroxypyridine moiety in karnamicin is proposed to be due to sequential operation of a hybrid polyketide synthase-nonribosomal peptide synthetase, two regioselective pyridine ring flavoprotein hydroxylases, and a methyltransferase. Based on AlphaFold protein structures predictions, molecular docking, and site-directed mutagenesis, we find that two pyridine hydroxylases deploy active site residues distinct from other flavoprotein monooxygenases to direct the chemo- and regioselective hydroxylation of the pyridine nucleus. Pleasingly, karnamicins show significant angiotensin-converting enzyme inhibitory activity with IC 50 values ranging from 0.24 to 5.81 μM, suggesting their potential use for the treatment of hypertension and related diseases.
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