Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics

Abstract

Post-translational acetylation of lysine residues has emerged as a key regulatory mechanism in all eukaryotic organisms. Originally discovered in 1963 as a unique modification of histones, acetylation marks are now found on thousands of nonhistone proteins located in virtually every cellular compartment. Here we summarize key findings in the field of protein acetylation over the past 20 years with a focus on recent discoveries in nuclear, cytoplasmic, and mitochondrial compartments. Collectively, these findings have elevated protein acetylation as a major post-translational modification, underscoring its physiological relevance in gene regulation, cell signaling, metabolism, and disease.

Figure 1.

Proposed reaction mechanism of spontaneous acetylation in the mitochondria.

Figure 2.

Structures of catalytic KAT domains from GNAT (human GCN5, blue, PDB: 1Z4R), MYST (human MOZ, orange, PDB: 2RC4), and KAT3A/B(CBP/p300) (human KAT3B(p300), gray, PDB: 3BIY) families. Acetyl-CoA is shown in cyan. Images rendered in Chimera (UCSF).

Figure 3.

Proposed reaction mechanism for GNAT family KATs.

Figure 4.

Proposed reaction mechanism for p300 family KATs.

Figure 5.

Structures of catalytic KDAC domains from KDAC (human KDAC2, red, PDB: 4LXZ) and Sirtuin (human SIRT1, purple, PDB: 4I5I families). KDAC zinc and Sirtuin NAD are shown in yellow. Images rendered in Chimera (UCSF).

Figure 6.

Proposed reaction mechanism for class I, II, and IV KDACs.

Figure 7.

Proposed reaction mechanism for class III KDACs/sirtuins. Reprinted with permission from ref . Copyright 2010 The Royal Society of Chemistry.

Figure 8.

Structures of acetylation reader domains: Bromodomain (human BRD4, black, PDB: 3UVW), double PHD (human DPF3, blue, PDB: 2KWJ), and YEATS (human AF9, yellow, PDB: 4TMP). Acetyl-lysine ligands shown in pink. Images rendered in Chimera (UCSF).

Figure 9.

Acetylome studies reveal the scope of biological functions regulated by acetylation in mammalian cells.

Figure 10.

Mechanisms driving acetylation dependent regulation of transcription factors.

Figure 11.

Selected chemical structures of KDAC inhibitors.

Figure 12.

Selected chemical structures of sirtuin activators.

Figure 13.

Selected chemical structures of sirtuin inhibitors.

Figure 14.

Selected chemical structures of KAT inhibitors.

Figure 15.

Selected chemical structures of BET inhibitors.