Lysine acetyltransferases (KATs) play a critical role in the regulation of gene expression, metabolism, and other key cellular functions. Disruption of acetylation-dependent signaling cascades represents an emerging paradigm in oncology. However, many aspects of the function of KATs remain enigmatic, including their metabolic regulation, their targetable role in cancer, and whether heretofore undiscovered KAT enzymes may exist. Such questions would be illuminated by methods enabling the rapid and global characterizaton of KAT enzymes in their endogenous settings. Here we describe the development and application of chemical proteomic methods capable of studying KATs in cellular contexts. Chemical affinity purification and unbiased LC-MS/MS profiling are applied to highlight an expanded landscape of orphan lysine acetyltransferases present in the human genome. These methods also enable quantitative measurements of KAT-small molecule interactions, providing novel insights into the regulation of these enzymes, and new assays for inhibitor development. Understanding how cellular acetylation is established is essential to rationally manipulate this process for therapeutic benefit. Chemoproteomic profiling provides a core platform for the discovery and investigation of KATs in cellular contexts, thereby accelerating efforts to define the biological function of acetylation and its targetable role in cancer and other diseases.

Chemoproteomic profiling of lysine acetyltransferases highlights an expanded landscape of catalytic acetylation

249th National Meeting (2015)

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