Molecular Basis of C–N Bond Cleavage by the Glycyl Radical Enzyme Choline Trimethylamine-Lyase

Journal Article · Sat Oct 01 00:00:00 EDT 2016 · Cell Chemical Biology

DOI:https://doi.org/10.1016/j.chembiol.2016.07.020· OSTI ID:1332564

Bodea, Smaranda; Funk, Michael A.; Balskus, Emily P.; Drennan, Catherine L.

We report that deamination of choline catalyzed by the glycyl radical enzyme choline trimethylamine-lyase (CutC) has emerged as an important route for the production of trimethylamine, a microbial metabolite associated with both human disease and biological methane production. Here, we have determined five high-resolution X-ray structures of wild-type CutC and mechanistically informative mutants in the presence of choline. Within an unexpectedly polar active site, CutC orients choline through hydrogen bonding with a putative general base, and through close interactions between phenolic and carboxylate oxygen atoms of the protein scaffold and the polarized methyl groups of the trimethylammonium moiety. These structural data, along with biochemical analysis of active site mutants, support a mechanism that involves direct elimination of trimethylamine. Lastly, this work broadens our understanding of radical-based enzyme catalysis and will aid in the rational design of inhibitors of bacterial trimethylamine production.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC), Basic Energy Sciences (BES)
• OSTI ID: 1332564
• Journal Information: Cell Chemical Biology, Vol. 23, Issue 10; ISSN 2451-9456
• Country of Publication: United States
• Language: ENGLISH