Enzymatic C-H Oxidation-Amidation Cascade in the Production of Natural and Unnatural Thiotetronate Antibiotics with Potentiated Bioactivity.
Enzymatic C-H Oxidation-Amidation Cascade in the Production of Natural and Unnatural Thiotetronate Antibiotics with Potentiated Bioactivity.
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DOI：
10.1002/anie.201705239
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发表时间：
2017-09-25
期刊：
影响因子：
--
通讯作者：
Moore BS
中科院分区：
文献类型：
--
作者：
Li J;Tang X;Awakawa T;Moore BS
生物合成酶对未反应的烃类的选择性活化激发了C-H键活化的新合成方法。在此，我们报告了前所未有的两步生物合成转化的硫代替曲霉素，硫代替曲酰胺C涉及串联氧化和酰胺化的一个不反应的乙基。我们详细介绍了硫代四酰胺C生物合成中的末端酰胺化的遗传和生物化学基础，其中涉及一个独特的适应细胞色素P450-酰胺转移酶对，并突出了第一个氧化-酰胺化酶级联反应，导致从化学惰性烷基选择性形成伯酰胺基团。由于硫代四酰胺C归因于乙酰胺基团和所涉及的不寻常酶学的抗生素效力增加了10倍，我们酶促询问了不同的硫代乳霉素类似物，并制备了与母体分子相比具有增强生物活性的非天然硫代四酰胺C类似物。酶促氧化-酰胺化级联反应：揭示硫代四酰胺C末端酰胺基团的生物化学起源，阐明了一种独特的细胞色素P450-酰胺转移酶对，该酶对选择性地和顺序地氧化和酰胺化一个不反应的乙基基团，导致抗生素效力的显着增加。这种酶对的底物混杂性为化学酶促合成提供了机会。
The selective activation of unreactive hydrocarbons by biosynthetic enzymes has inspired new synthetic methods in C–H bond activation. Herein, we report the unprecedented two-step biosynthetic conversion of thiotetromycin to thiotetroamide C involving the tandem oxidation and amidation of an unreactive ethyl group. We detail the genetic and biochemical basis for the terminal amidation in thiotetroamide C biosynthesis, which involves a uniquely adapted cytochrome P450-amidotransferase enzyme pair and highlights the first oxidation-amidation enzymatic cascade reaction leading to the selective formation of a primary amide group from a chemically inert alkyl group. Motivated by the ten-fold increase in antibiotic potency of thiotetroamide C ascribed to the acetamide group and the unusual enzymology involved, we enzymatically interrogated diverse thiolactomycin analogues and prepared an unnatural thiotetroamide C analogue with potentiated bioactivity compared to the parent molecule. Enzymatic oxidation-amidation cascade: Uncovering the biochemical genesis of the terminal amide group of thiotetroamide C illuminated a uniquely adapted cytochrome P450-amidotransferase enzyme pair that selectively and sequentially oxidizes and amidates an unreactive ethyl group, leading to a significant increase in antibiotic potency. Substrate promiscuity of this enzyme pair provides an opportunity in chemoenzymatic synthesis.
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影响因子：
56.9
作者：
Chen, Mark S.;White, M. Christina
通讯作者：
White, M. Christina
DOI：
10.1073/pnas.1519695113
发表时间：
2016-04-05
影响因子：
11.1
作者：
El Gamal, Abrahim;Agarwal, Vinayak;Moore, Bradley S.
通讯作者：
Moore, Bradley S.
影响因子：
56.9
作者：
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通讯作者：
Sanford, Melanie S.
影响因子：
18.2
作者：
Hartwig JF;Larsen MA
通讯作者：
Larsen MA
影响因子：
15
作者：
Dydio, Pawel;Key, Hanna M.;Hartwig, John F.
通讯作者：
Hartwig, John F.