Histone-lysine N-methyltransferase (KMT)

Histone-lysine N-methyltransferases (KMTs) are a large and diverse family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-L-methionine (SAM) to specific lysine residues on histone proteins, such as H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20 (UniProt, 2024). These modifications serve as critical epigenetic marks that regulate chromatin structure and gene accessibility, with different marks associated with either transcriptional activation or repression (Nature Reviews Drug Discovery, 2022). For instance, EZH2-mediated H3K27 trimethylation is a hallmark of gene silencing, while DOT1L-mediated H3K79 methylation is linked to active transcription (PubMed, 2023). Dysregulation of KMTs is a common feature in many diseases, particularly cancer, where mutations or overexpression can lead to the silencing of tumor suppressor genes or the activation of oncogenes (NIH, 2023). Therapeutic strategies targeting KMTs involve small-molecule inhibitors that block the enzyme's catalytic activity, often by competing with SAM or the histone substrate (PubChem, 2024). While these inhibitors, such as the FDA-approved Tazemetostat, show promise in treating hematological and solid tumors, challenges include achieving high selectivity among family members and managing potential long-term effects on global gene expression (FDA, 2020).

Other names

Lysine methyltransferaseProtein-lysine N-methyltransferaseHMTHistone methyltransferaseKMT

Inhibition of the methyltransferase activity by competing with the S-adenosyl-L-methionine (SAM) cofactor or the histone substrate, thereby preventing the transfer of methyl groups to lysine residues and modulating gene expression.