Lysine methyltransferases (KMTs) and arginine methyltransferases (RMTs) have a common mechanism of catalysis. Both families transfer a methyl group from a common donor, S-adenosyl-L-methionine (SAM), to the nitrogen atom on the epsilon-amino group of lysine or arginine (Smith & Denu 2009) using a bimolecular nucleophillic substitution (SN2) methyl transfer mechanism (Smith & Denu 2009, Zhang & Bruice 2008). All human KMTs except DOT1L (KMT4) (Feng et al. 2002, van Leeuwen et al. 2002, Lacoste et al. 2002) have a ~130 amino acid catalytic domain referred to as the SET domain (Del Rizzo & Trievel 2011, Dillon et al. 2005, Herz et al. 2013).
Some KMTs selectively methylate a particular lysine residue on a specific histone type. The extent of this methylation (mono-, di- or tri-methylation) also can be stringent (Herz et al. 2013, Copeland et al. 2009). Many KMTs also have non-histone substrates (Herz et al 2013), which are not discussed in this module.
The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any processing. Histone literature typically refers to specific residues by numbers which are determined after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared to the histone literature.
SET domain-containing proteins are classified in one of 7 families (Dillon et al. 2005). First to be discovered were the SUV39 family named after founding member SUV39H1 (KMT1A), which selectively methylates lysine-10 of histone H3 (H3K9) (Rea et al. 2000). Family member EHMT2 (KMT1C, G9A) is the predominant H3K9 methyltransferase in mammals (Tachibana et al. 2002). SETDB1 (KMT1E, ESET) also predominantly methylates H3K9, most effectively when complexed with ATF7IP (MCAF, hAM) (Wang et al. 2003).
SETD2 (KMT3A, HYPB), a member of the SET2 family, specifically methylates histone H3 lysine-37 (H3K36) (Sun et al. 2005). WHSC1 (KMT3G, NSD2, MMSET) a member of the same family, targets H3K36 when provided with nucleosome substrates but also can methylate histone H4 lysine-45 when octameric native or recombinant nucleosome substrates are provided (Li et al. 2009); dimethylation of histone H3 at lysine-37 (H3K36me2) is thought to be the principal chromatin-regulatory activity of WHSC1 (Kuo et al. 2011). Relatives NSD1 (KMT3B) and WHSC1L1 (KMT3F, NSD3) also methylate nucleosomal H3K36. NSD1 is active on unmethylated or a mimetic monomethylated H3K36, but not di- or trimethylated H3K36 mimetics (Li et al. 2009). Human SETD7 (KMT7, SET7/9), not classified within the 7 SET-domain containing families, mono-methylates lysine-5 of histone H3 (H3K4) (Xiao et al. 2003).