Characterization of the Stereoselective P450 Enzyme BotCYP Enables the In Vitro Biosynthesis of the Bottromycin Core Scaffold,Journal of the American Chemical Society

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Characterization of the Stereoselective P450 Enzyme BotCYP Enables the In Vitro Biosynthesis of the Bottromycin Core Scaffold
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-11-28 , DOI: 10.1021/jacs.0c10361
Sebastian Adam ₁ , Laura Franz ₁ , Mohammed Milhim ₂ , Rita Bernhardt ₂ , Olga V. Kalinina _{3,

4} , Jesko Koehnke _{1,

5}

Affiliation

Bottromycins are ribosomally synthesized and post-translationally modified peptide natural product antibiotics that are effective against high-priority human pathogens such as methicillin-resistant Staphylococcus aureus. The total synthesis of bottromycins involves at least 17 steps, with a poor overall yield. Here, we report the characterization of the cytochrome P450 enzyme BotCYP from a bottromycin biosynthetic gene cluster. We determined the structure of a close BotCYP homolog and used our data to conduct the first large-scale survey of P450 enzymes associated with RiPP biosynthetic gene clusters. We demonstrate that BotCYP converts a C-terminal thiazoline to a thiazole via an oxidative decarboxylation reaction and provides stereochemical resolution for the pathway. Our data enable the two-pot in vitro production of the bottromycin core scaffold and may allow the rapid generation of bottromycin analogues for compound development.

中文翻译：

立体选择性 P450 酶 BotCYP 的表征使博曲霉素核心支架的体外生物合成成为可能

Bottroomycins 是核糖体合成和翻译后修饰的肽天然产物抗生素，可有效对抗高优先级人类病原体，如耐甲氧西林金黄色葡萄球菌。bottroomycins 的全合成至少需要 17 个步骤，总体收率较差。在这里，我们报告了来自肉毒杆菌素生物合成基因簇的细胞色素 P450 酶 BotCYP 的表征。我们确定了一个紧密的 BotCYP 同源物的结构，并使用我们的数据对与 RiPP 生物合成基因簇相关的 P450 酶进行了第一次大规模调查。我们证明 BotCYP 通过氧化脱羧反应将 C 端噻唑啉转化为噻唑，并为该途径提供立体化学分辨率。

更新日期：2020-11-28

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