Accumulating evidence shows that bacteria residing within the human intestinal tract (gut microbiome) influence host physiology and metabolism and we have previously shown that the gut microbiome is altered in patients with type 2 diabetes (T2D). However, there has only been limited knowledge on how the microbiome contributes to T2D development. This proposal was based on the overarching hypothesis that the gut microbiome affects host metabolism through the production of key metabolites, which enter the body and modulate peripheral metabolism. Only a few gut microbiome-generated metabolites affecting host physiology have yet been identified, but we recently identified a microbially produced metabolite from the amino acid histidine, imidazole propionate (ImP) to be elevated in patients with prediabetes and T2D. Furthermore, administration of the metabolite to mice caused insulin resistance, suggesting that inhibition of the enzyme producing ImP, urocanate reductase, may be a plausible approach to treat T2D. Also, an additional predicted advantage of targeting microbial enzymes is that they are less likely to cause adverse events and do not require systemic uptake.
Based on these findings we have synthesized and screened more than 40 compounds and identified important features that are important for production of ImP. This will allow us to produce a second generation of compounds that can have stronger inhibitory power. To further improve the design of potential inhibitors of urocanate reductase we crystalized the protein, e.gcr. the domain with the active site and FAD binding domain in E. coli and determined the structure of urocanate reductase using X-ray crystallography to very high
