KAT(ching) metabolism by the tail: insight into the links between lysine acetyltransferases and metabolism

Abstract

Post-translational modifications of histones elicit structural and functional changes within chromatin that regulate various epigenetic processes. Epigenetic mechanisms rely on enzymes whose activities are driven by coenzymes and metabolites from intermediary metabolism. Lysine acetyltransferases (KATs) catalyze the transfer of acetyl groups from acetyl-CoA to epsilon amino groups. Utilization of this critical metabolite suggests these enzymes are modulated by the metabolic status of the cell. This review highlights studies linking KATs to metabolism. We cover newly identified acyl modifications (propionylation and butyrylation), discuss the control of KAT activity by cellular acetyl-CoA levels, and provide insights into how acetylation regulates metabolic proteins. We conclude with a discussion of the current approaches to identifying novel KATs and their metabolic substrates.

Figure 1

KATs utilize sequential (direct attack) mechanism of acetylation. “R” denotes various alkyl chains that can be accommodated by KATS. Carboxylate group is a general base (aspartate or glutamate) that facilitates abstraction of proton on ε-amine of lysine. Following attack of acyl-group on acyl-CoA by unprotonated lysine, a putative tetrahedral intermediate forms. Collapse of this intermediate results in the formation of acylated lysine on protein and CoA products.

Figure 2

Summary of confirmed sites of acetylation (Ac), propionylation (Prop) and butyrylation (Buty) for yeast histones^[19]. Propionylation and butyrylation confirmed in vivo are demarcated with *. The first 30 N-terminal residues are listed and globular domains shown in grey.

Figure 3

Metabolism and protein acylation are intimately linked through metabolites acetyl-CoA, propionyl-CoA and butyryl-CoA. ACL- ATP citrate lyase; ACS- acetyl-CoA synthethase; KAT- lysine acyltransferase; PDH-pyruvate dehydrogese complex. Pathways leading to the production of propionyl-CoA and butyryl-CoA production are not shown.