State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
J Org Chem. 2020 Jul 2;85(13):8673-8682. doi: 10.1021/acs.joc.0c01113. Epub 2020 Jun 16.
Since pepticinnamin E was discovered almost 30 years ago, no other pepticinnamin family of natural products has been reported to date. Here, we report the discovery of pepticinnamins G-I (-) from a marine sp. PKU-MA01144 and pepticinnamins J-M (-) from several mutants, and these new compounds contain different -methyl-l-alanine and l-tyrosine residues compared to pepticinnamin E. Genome sequencing, heterologous expression, gene deletion, and reconstitution of enzymatic reaction in vitro identified the biosynthetic gene cluster of - and first experimentally established the biosynthesis of the nonproteinogenic 2-chloro-3-hydroxy-4-methoxy-l-phenylalanine residue by a biopterin-dependent hydroxylase Pep10, an O-methyltransferase Pep9, and a flavin-dependent halogenase Pep1. The biosynthetic research and heterologous expression system in this study set the stage for pathway engineering for more pepticinnamins generation in the future.
自近 30 年前发现肠抗菌素 E 以来，迄今为止尚未有其他肠抗菌素天然产物家族被报道。在这里，我们报道了从海洋 sp. PKU-MA01144 中发现的肠抗菌素 G-I（-）和从几种突变体中发现的肠抗菌素 J-M（-），这些新化合物与肠抗菌素 E 相比，含有不同的 -甲基-l-丙氨酸和 l-酪氨酸残基。基因组测序、异源表达、基因缺失和体外酶反应的重建确定了 -和 的生物合成基因簇，并首次通过生物蝶呤依赖性羟化酶 Pep10、O-甲基转移酶 Pep9 和黄素依赖性卤化酶 Pep1 实验性地建立了非蛋白氨基酸 2-氯-3-羟基-4-甲氧基-l-苯丙氨酸残基的生物合成。本研究中的生物合成研究和异源表达系统为未来更多肠抗菌素的产生提供了途径工程的基础。
