Epigenetics

Epigenetics pertains to the mechanisms that produce inheritable changes in the functional state of DNA, especially gene expression, without changing the DNA sequence. Modification of epigenetic signaling is involved in multiple human diseases, including a range of chronic and life-threatening conditions.^[1] Activators or inhibitors of epigenetic modification enzymes provide the pharmacological tools to investigate the biological consequences of chromatin modifications. Epigenetics primarily includes DNA methylation and posttranslational histone modifications. DNA methyltransferases are a family of enzymes that catalyze the transfer of a methyl group to DNA. In mammals, the DNMT family includes three active enzymes: DNMT1, DNMT3A and DNMT3B as well as one inactive enzyme, DNMT3L.^[2] DNA methyltransferase inhibitors include nucleoside analogs, which require DNA incorporation for DNMT inhibition and non-nucleoside analog which inhibit DNMT directly, without DNA incorporation. Histone methyltransferases (HMT) are histone-modifying enzymes, including histone-lysine N-methyltransferase and histone-arginine N-methyltransferase. HMTs catalyze the transfer of one, two or three methyl groups to lysine and arginine residues of histone proteins. Modulators or inhibitors involved in the histone methylation process include Histone Lysine Methyltransferase (HKMT) inhibitors, Histone Lysine Demethylase inhibitors, and Protein Arginine Methyltransferase (PRMT) modulators.^[3]
Histone deacetylases (HDACs) are divided into five phylogenetic classes: class I comprises HDAC1, HDAC2, HDAC3 and HDAC8; class IIa comprises HDAC4, HDAC5, HDAC7 and HDAC9; class IIb comprises HDAC6 and HDAC10; class III comprises the sirtuins SIRT1–SIRT7; and class IV contains HDAC11. Inhibitors of Class I and II HDACs mainly correspond to four groups on the basis of their chemical structures: short-chain fatty acid inhibitors, hydroxamic acid inhibitors, benzamide inhibitors and cyclic tetrapeptides. Many natural products also serve as HDAC modulators, including resveratrol, a well-known activator of SIRT1. All HDAC inhibitors occupy the canonical acetyl-lysine channel of HDACs.^[4] Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyllysine. Inhibitors of HATs have a potential role in interceding in the pathology of cancer, asthma, COPD and viral infection.^[5]

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