Figure 6.

Plausible mechanisms of actin histidine Nτ-methylation by SETD3. The enzyme catalyzes the methylation of Nτ nitrogen atom of H73 residue in actin. The methyl group of AdoMet can be transferred only to the deprotonated nitrogen atom. Since each of the two nitrogen atoms of the imidazole ring can hypothetically be protonated, the side chain of N256 residue of SETD3 stabilizes the Nπ nitrogen atom of H73 in the protonated form [32]. Consequently, it enhances the nucleophilicity of the lone pair of electrons present at the deprotonated Nτ nitrogen that may then attack the methyl group of AdoMet.