UCSF

While the composition of the gut microbiota varies markedly among humans, the functional ramifications of these differences have only begun to be explored. In the course of characterizing the reductive metabolism of aromatic amino acids by a common gut Firmicute, Clostridium sporogenes, we made the unanticipated discovery that this bacterium decarboxylates tryptophan to form the beta-arylamine neurotransmitter tryptamine, an enzymatic activity that is exceedingly rare among bacteria. Using a combination of genetics and biochemistry, we identify and characterize the PLP-dependent decarboxylase responsible for this activity, CLOSPO_02083, which had been misannotated as a tyrosine decarboxylase. To explore whether tryptophan decarboxylation is more widely distributed among the microbiota than previously known, we carried out a phylogeny-informed screen of ~15 putative bacterial decarboxylases. This screen revealed another novel tryptophan decarboxylase, RUMGNA_01526, which is phylogenetically distinct from CLOSPO_02083. Crystal structures of RUMGNA_01526 in its native form and bound to the inhibitor (S)-alpha-fluoromethyltryptophan, the first structures of a bacterial PLP-dependent decarboxylase, reveal the determinants of selectivity for the larger substrate Trp, including a flexible catalytic loop that controls access to the substrate-binding pocket. A computational analysis of whole-genome shotgun sequencing data from the Human Microbiome Project demonstrates that at least 10% of the human population harbors one of these two tryptophan decarboxylases in their gut community. By revealing a novel biochemical activity that is present in the gut communities of some but not all individuals, our results open a new line of investigation into the production and function of beta-arylamines by the human microbiota.