Methyltransferases (EC 2.1.1.-) constitute an important class of enzymes present in every life form. They transfer a methyl group most frequently from S-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such as nitrogen, oxygen, sulfur or carbon leading to S-adenosyl-L-homocysteine (AdoHcy) and a methylated molecule. The substrates that are methylated by these enzymes cover virtually every kind of biomolecules ranging from small molecules, to lipids, proteins and nucleic acids. Methyltransferases are therefore involved in many essential cellular processes including biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing [1,2,3]. More than 230 different enzymatic reactions of methyltransferases have been described so far, of which more than 220 use SAM as the methyl donor [E1]. A review published in 2003 [2] divides all methyltransferases into 5 classes based on the structure of their catalytic domain (fold):

• class I: Rossmann-like α/β see <PDOC51555>
• class II: TIM β/α-barrel α/β
• class III: tetrapyrrole methylase α/β
• class IV: SPOUT α/β see <PDOC51604>
• class V: SET domain all β

A more recent paper [3] based on a study of the Saccharomyces cerevisiae methyltransferome argues for four more folds:

• class VI: transmembrane all α see <PDOC51598>
• class VII: DNA/RNA-binding 3-helical bundle all α
• class VIII: SSo0622-like α+β
• class IX: thymidylate synthetase α+β

Class V proteins contain the SET domain (see <PDOC50280>) usually flanked by other domains forming the so-called pre- and post-SET regions. Except the members of the STD3 family which N-methylate histidine in β-actin (EC 2.1.1.85) (see <PDB:6ICT>) [4,5], enzymes belonging to this class N-methylate lysine in proteins. Most of them are histone methyltransferases (EC 2.1.1.43) like the histone H3-K9 methyltransferase dim-5 (see <PDB:1ML9>) or the histone H3-K4 methyltransferase SETD7 (see <PDB:1H3I>) [3,6]. Some others methylate the large subunit of the enzyme ribulose-bisphosphate-carboxylase/oxygenase (RuBisCO) (EC 2.1.1.127) in plants; in these enzymes the SET domain is interrupted by a novel domain [4]. Cytochrome c lysine N-methyltransferases (EC 2.1.1.59) do not possess a SET domain, or at least not a SET domain detected by any of the detection methods; however they do display a SET-like region and for this reason they are also assigned to this class [7].

Some enzymatic activities known to belong to the Class V superfamily:

• SETD3 actin-histidine N-methyltransferase (EC 2.1.1.85). Orthologues of the protein SETD3 are present in animals, plants and certain fungi, but not in the proteomes of the amoeboflagellate Neisseria gruberi and yeast species.
• TRX/MLL histone-lysine N-methyltransferase (EC 2.1.1.43).
• Suvar4-20 histone-lysine N-methyltransferase (EC 2.1.1.43).
• SET2 histone-lysine N-methyltransferase (EC 2.1.1.43).
• PR/SET histone-lysine N-methyltransferase (EC 2.1.1.43).
• Suvar3-9 histone-lysine N-methyltransferase (EC 2.1.1.43).
• EZ histone-lysine N-methyltransferase (EC 2.1.1.43).
• SET7 histone-lysine N-methyltransferase (EC 2.1.1.43).
• Plant LSMT protein-lysine methyltransferase. LSMT homologs from plants display different substrate specificities, with targets involved in carbon metabolism.
• [Cytochrome c]-lysine N-methyltransferase (EC 2.1.1.59).

The profiles we developed to identify Class V SAM-dependent methyltransferases families are directed against whole length proteins.