Epigenetic regulation by endogenous metabolite pharmacology

Altered metabolite levels can drive epigenetic changes critical to development and disease. However, in many cases the specific protein-metabolite interactions that underlie this process remain enigmatic. In this review, we make the case that this fundamental missing information may be discovered by applying the tools of modern drug target validation to study endogenous metabolite pharmacology. We detail examples in which chemical proteomics has been applied to gain new insights into reversible and covalent metabolite signaling mechanisms, using acetyl-CoA and fumarate as case studies. Finally, we provide a brief survey of nascent chemical biology methods whose application to the study of endogenous metabolite pharmacology may further advance the field.