The anaerobic conversion of choline to trimethylamine (TMA) by the human gut microbiota has been linked to multiple human diseases. The potential impact of this microbial metabolic activity on host health has inspired multiple efforts to identify small molecule inhibitors. Here, we use information about the structure and mechanism of the bacterial enzyme choline TMA-lyase (CutC) to develop a cyclic choline analog that inhibits the conversion of choline to TMA in bacterial whole cells and in a complex gut microbial community. In vitro biochemical assays and a crystal structure suggest that this analog is a competitive, mechanism-based inhibitor. This work demonstrates the utility of structure-based design to access inhibitors of radical enzymes from the human gut microbiota.

中文翻译：

---

发现一种抑制人肠道细菌厌氧胆碱代谢的环状胆碱类似物

人类肠道微生物群将胆碱厌氧转化为三甲胺 (TMA) 与多种人类疾病有关。这种微生物代谢活动对宿主健康的潜在影响激发了多种努力来确定小分子抑制剂。在这里，我们使用有关细菌酶胆碱 TMA 裂解酶 (CutC) 的结构和机制的信息来开发一种环状胆碱类似物，可抑制细菌全细胞和复杂肠道微生物群落中胆碱向 TMA 的转化。体外生化分析和晶体结构表明这种类似物是一种竞争性的、基于机制的抑制剂。这项工作证明了基于结构的设计从人类肠道微生物群中获取自由基酶抑制剂的实用性。