Jumonji C domain-containing histone lysine demethylase (JmjC KDM)

Jumonji C (JmjC) domain-containing histone lysine demethylases are a major class of epigenetic enzymes that catalyze the removal of methyl groups from lysine residues on histone proteins (Kooistra and Helin, 2012, PubMed: 22487657). These enzymes are characterized by their dependence on Fe(II) and 2-oxoglutarate (2-OG) as cofactors, utilizing an oxidative mechanism to demethylate mono-, di-, and tri-methylated substrates (Markolovic et al., 2016, PubMed: 26814321). They play a fundamental role in regulating gene expression, chromatin architecture, and cellular identity during development and differentiation. In many pathological contexts, particularly oncology, JmjC KDMs are often overexpressed or mutated, leading to the aberrant silencing of tumor suppressor genes or the activation of oncogenic pathways (Hoffmann et al., 2012, PubMed: 22539170). Therapeutic strategies primarily involve the development of small-molecule inhibitors that competitively bind to the 2-OG or iron-binding sites within the catalytic JmjC domain. While promising, the high degree of structural homology among the 60+ members of the 2-OG oxygenase superfamily presents significant challenges for achieving the selectivity required to minimize off-target effects and systemic toxicity.

Other names

JmjC-KDMs2-oxoglutarate-dependent lysine demethylasesFe(II)- and 2-oxoglutarate-dependent oxygenasesHistone demethylase (JmjC-containing)

Competitive inhibition of the 2-oxoglutarate cofactor or chelation of the catalytic Fe(II) ion within the JmjC domain.