Structural highlights
Function
CUTC_OLEA2 Glycine radical enzyme that catalyzes the cleavage of a C-N bond in choline, producing trimethylamine (TMA) and acetaldehyde (PubMed:23151509, PubMed:24854437). Is involved in the anaerobic choline utilization pathway that allows D.alaskensis to grow on choline as a source of carbon and energy (PubMed:23151509). Is strictly specific for choline as substrate (PubMed:24854437).[1] [2]
Publication Abstract from PubMed
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.
Discovery of a Cyclic Choline Analog That Inhibits Anaerobic Choline Metabolism by Human Gut Bacteria.,Bollenbach M, Ortega M, Orman M, Drennan CL, Balskus EP ACS Med Chem Lett. 2020 Mar 25;11(10):1980-1985. doi:, 10.1021/acsmedchemlett.0c00005. eCollection 2020 Oct 8. PMID:33062182[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21307-12. doi:, 10.1073/pnas.1215689109. Epub 2012 Nov 14. PMID:23151509 doi:http://dx.doi.org/10.1073/pnas.1215689109
- ↑ Craciun S, Marks JA, Balskus EP. Characterization of choline trimethylamine-lyase expands the chemistry of glycyl radical enzymes. ACS Chem Biol. 2014 Jul 18;9(7):1408-13. doi: 10.1021/cb500113p. Epub 2014 Jun 2. PMID:24854437 doi:http://dx.doi.org/10.1021/cb500113p
- ↑ Bollenbach M, Ortega M, Orman M, Drennan CL, Balskus EP. Discovery of a Cyclic Choline Analog That Inhibits Anaerobic Choline Metabolism by Human Gut Bacteria. ACS Med Chem Lett. 2020 Mar 25;11(10):1980-1985. PMID:33062182 doi:10.1021/acsmedchemlett.0c00005
