Metabolite Sensing and Regulation of Protein Function After the human genome is sequenced, one of the most important challenges in biomedical research is to understand how gene expression changes in response to various signals and stresses. In other words, understanding cell signaling mechanisms is of critical importance to understand life processes. This proposal focuses on how mammalian cells sense certain metabolites and use that information to regulate protein function. Common cellular metabolites, such as co-enzyme A, glutathione, and nicotinamide adenine dinucleotides, play important roles in various metabolic pathways. Many protein post-translational modifications also use these metabolites. Maintaining the concentrations of these metabolites is thus critically important. Cells and organisms must be able to sense these metabolites and use the information to regulate biological processes. However, very little is known about the sensing mechanisms for these metabolites. In this MIRA application, I will focus on using chemical biology techniques to identify how mammalian cells sense common metabolites to regulate protein function. Preliminary results indicate that this is a highly interesting and exciting area that warrant much more investigation. This a completely new research direction for my laboratory and is distinct from my previous and HHMI-supported research. The proposed research will identify many novel regulatory mechanisms of protein function by small molecule metabolites. This will in turn provide a better understanding of cell signaling and address one of the most important challenges in biomedical sciences in the postgenomic era. These regulatory mechanisms can also directly impact the development of therapeutics as they will help to develop allosteric inhibitors or activators of proteins.