Lysine acetyltransferase 2A (KAT2A) (KAT2A)

Lysine acetyltransferase 2A (KAT2A), commonly referred to as GCN5, is a key epigenetic enzyme that catalyzes the transfer of an acetyl group to lysine residues on histone H3 and various non-histone proteins (UniProt: O94851). A major regulatory role of GCN5 is the acetylation of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master coactivator of mitochondrial biogenesis and metabolic gene expression (PubMed: 16713566). Acetylation by GCN5 serves as a molecular switch that inactivates PGC-1α, thereby reducing mitochondrial oxidative capacity and promoting hepatic gluconeogenesis (PubMed: 17662185). In the context of metabolic diseases like Type 2 Diabetes and obesity, GCN5 activity is often dysregulated, making it a therapeutic target for small-molecule inhibitors aimed at restoring PGC-1α activity to improve insulin sensitivity. Furthermore, GCN5 is implicated in oncology, where it functions as a coactivator for oncogenic transcription factors such as MYC and E2F, driving cell cycle progression and tumor growth (PubMed: 27501443). While several tool compounds like MB3 and CPTH2 exist, developing selective inhibitors remains a challenge due to the enzyme's structural similarity to other acetyltransferases and its essential role in global gene regulation.

Other names

GCN5GCN5L2General control of amino acid synthesis protein 5-like 2hGCN5Histone acetyltransferase KAT2A

Inhibition of the acetyltransferase activity of GCN5 to prevent the acetylation and subsequent inactivation of PGC-1α, thereby enhancing mitochondrial function and metabolic homeostasis.