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 co-enzymes and metabolites from intermediary metabolism. Lysine acetyltransferases (KATs) catalyze the transfer of acetyl groups from acetyl-CoA to epsilon amine 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. Lastly, we conclude with a discussion of the current approaches for identifying novel KATs and their metabolic substrates.

Structural basis for acyl group discrimination by human Gcn5L2

“…Combined with the observation that free CoA is present at roughly equimolar concentrations to acetyl-CoA in cells (Gao et al, 2007;Lee et al, 2014), it is plausible that the ratio of acetyl-CoA to CoA may modulate KAT activity (Albaugh et al, 2011). Interestingly, a recent study profiling the acyl chain specificity of Gcn5 observed potent inhibition by long fatty acyl-CoA molecules like palmitoyl-CoA (Montgomery et al), further supporting the idea that acyl-CoA molecules may function as natural KAT inhibitors.…”

“…Coenzyme A is a common nucleotide cofactor that carries many different kinds of acyl groups in vivo (King & Reiss, 1985) and many metabolic processes produce or consume acyl-CoAs (Albaugh et al, 2011). As a result, intracellular concentrations of different acyl-CoA species change in response to metabolic fluctuations (Hosokawa et al, 1986;Palladino et al, 2012;King & Reiss, 1985).…”

“…For example, measurements of the intracellular concentration of acetyl-CoA vary based on nutrient availability, and range from 3 to 30 µM in yeast (Cai et al, 2011;Weinert, 2014) and 2 to 13 µM in human cells (Lee et al, 2014). With a K m for acetyl-CoA of 0.91 ± 0.09 µM (Figure 5A), acetyl-CoA availability may regulate the activity of human Gcn5 (Albaugh et al, 2011). Consistent with this, Gcn5-catalyzed histone acetylation is induced under growth conditions with high intracellular levels of acetyl-CoA (Cai et al, 2011).…”

Metabolic sensors and their interplay with cell signalling and transcription

“…Propionyl-CoA and butyryl-CoA, like acetyl-CoA, are both high-energy products of fatty acid metabolism and are produced through similar chemical reactions [92]. Propionylation and butyrylation have been described on several lysine residues in histones H3, H4 and H2B, as well as in other non-histone proteins [93].…”

Metabolic Signaling to Chromatin

“…2). The nuclear/cytosolic pool of acetyl-CoA, responsible for protein acetylation and fatty acid synthesis, is produced by two enzymes in metazoans: the acetyl-CoA synthetase 1 (AceCS1) and ATP-citrate lyase (ACL) (Albaugh et al 2011). ACL uses citrate ( produced during the tricarboxylic acid [TCA] cycle) as a substrate for the production of acetyl-CoA, whereas AceCS1 uses acetate.…”