2YBP

Jumonji Domain protein 2A (JMJD2A or lysine-specific demethylase 4A, KDM4A) is a 2-oxoglutarate dependent oxygenase which catalyses the hydroxylation of methyl groups present on lysine residues within histone protein 3, utilising a Fe(II) dependent redox reaction, with spontaneous deformylation to produce the demethylated lysine and formaldehyde. The enzyme catalyses the removal of methyl groups specifically from lysine residues K9 and K36. JMJD2A has been shown to be over-expressed relative to normal physiological levels in several cancers, and is of interest for its influence over epigenetic factors associated with cancer progression.

The enzyme substrate specificity is determined by amino acids within the JMJD2A active site, and also the flexibility of residues positioned around the reactive lysine in the peptide backbone. The enzyme is most active with the tri-methyl substrate. Each of the three methyl groups binds in a discrete pocket, restricting rotation around the functional group and demethylation proceeds rapidly. In the presence of two methyl groups, the functional groups can flip between a more reactive and less reactive pocket, one which binds methyl groups weakly, but closer to the reactive Fe(II), and vice versa. JMJD2A is not active towards the mono-methyl lysine substrate. The single methyl group stays bound to the less reactive pocket, and cannot be demethylated.