Radical Chemistry in the Human Gut: Discovery of Choline Trimethylamine‐Lyase

The collection of microorganisms that inhabit the human gastrointestinal tract, our gut microbiota, has an extensive set of metabolic capabilities that directly impact human health. Our research seeks to discover and understand the molecular basis of disease‐associated metabolic pathways from the human microbiome. One example under investigation is the catabolism of the essential nutrient choline by anaerobic microbes. Gut bacteria break down choline in an entirely different manner than human cells, cleaving its C–N bond to produce trimethylamine (TMA), which is subsequently oxidized to trimethylamine N ‐oxide by liver enzymes. This microbial‐human co‐metabolic pathway has been linked to several diseases, including non‐alcoholic fatty liver disease and atherosclerosis. Using a genome mining strategy, we recently identified the first gene cluster responsible for anaerobic choline utilization (the cut gene cluster). We verified the functional role of this cluster using both genetic and heterologous expression approaches. These studies revealed that the key C–N bond cleavage step involved in choline breakdown is catalyzed by choline trimethylamine‐lyase (CutC), a new type of glycyl radical enzyme. This reaction is unprecedented chemistry for this enzyme family. We confirmed the activity of the purified choline TMA‐lyase and its activating protein in vitro , observing that CutC is exquisitely specific for choline cleavage. Currently, we are investigating the mechanism of the CutC‐catalyzed reaction, with the ultimate goal of designing small molecule inhibitors for this enzymatic transformation.