Center of Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0204, USA.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Angew Chem Int Ed Engl. 2017 Sep 25;56(40):12234-12239. doi: 10.1002/anie.201705239. Epub 2017 Sep 1.
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.
生物合成酶对非反应性碳氢化合物的选择性激活激发了 C-H 键活化的新合成方法。在此，我们报告了硫替莫环素到硫替特罗酰胺 C 的前所未有的两步生物合成转化，其中涉及非反应性乙基的串联氧化和酰胺化。我们详细介绍了硫替特罗酰胺 C 生物合成中末端酰胺化的遗传和生化基础，其中涉及到独特适应的细胞色素 P450-酰胺转移酶对，突出了第一个氧化-酰胺酶级联反应，导致从化学惰性烷基选择性形成伯酰胺基。受硫替特罗酰胺 C 的抗生素效力提高十倍归因于乙酰胺基和涉及的不寻常酶学的启发，我们通过酶促方法研究了不同的硫内酯霉素类似物，并制备了一种具有增强生物活性的非天然硫替特罗酰胺 C 类似物，与母体分子相比。
