Scheme 1.

Outline mechanism of KDM4A‐catalysed demethylation. After binding of 2OG to the ferrous iron at the active site, the histone substrate binds. O₂ then coordinates to the iron, thereby initiating an oxidative decarboxylation reaction, forming succinate, CO₂ and a reactive iron(IV)‐oxo intermediate. Insertion of the iron(IV)‐bound oxygen atom into a histone methyl C−H bond occurs, with resultant reduction of the iron(IV) to iron(II). The hemiaminal product on the histone then fragments, giving the demethylated product and formaldehyde. Inset. A view of an X‐ray crystal structure of KDM4A complexed with Ni (substituting for Fe^II, green)), N‐oxalylglycine (NOG; a 2OG analogue, blue) and a histone H3 fragment peptide N ^ϵ‐trimethylated at Lys9 (red). Lys241 is shown in pale green (PDB ID: 2OQ6).