Citation

Bollenbach M, Ortega M, Orman M, Drennan CL, Balskus EP. ACS Med. Chem. Lett. 2020; 11(10): 1980-1985.

Copyright

(Copyright © 2020, American Chemical Society)

DOI

10.1021/acsmedchemlett.0c00005

PMID

unavailable

Abstract

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. © 2020 American Chemical Society.

Language: en

Keywords

priority journal; nonhuman; suicide substrate; crystal structure; Article; in vitro study; choline; intestine flora; microbial community; anaerobic metabolism; cardiometabolic disease; Gut microbiota; lyase; small molecule inhibitor; trimethylamine; whole cell