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  divides all
methyltransferases into 5 classes based on the structure of their catalytic
- 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  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
126.96.36.199) (see <PDB:6ICT>) [4,5], enzymes belonging to this class N-methylate
lysine in proteins. Most of them are histone methyltransferases (EC 188.8.131.52)
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 184.108.40.206) in plants; in these enzymes the SET domain is
interrupted by a novel domain . Cytochrome c lysine N-methyltransferases
(EC 220.127.116.11) 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 .
Some enzymatic activities known to belong to the Class V superfamily:
- SETD3 actin-histidine N-methyltransferase (EC 18.104.22.168). 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 22.214.171.124).
- Suvar4-20 histone-lysine N-methyltransferase (EC 126.96.36.199).
- SET2 histone-lysine N-methyltransferase (EC 188.8.131.52).
- PR/SET histone-lysine N-methyltransferase (EC 184.108.40.206).
- Suvar3-9 histone-lysine N-methyltransferase (EC 220.127.116.11).
- EZ histone-lysine N-methyltransferase (EC 18.104.22.168).
- SET7 histone-lysine N-methyltransferase (EC 22.214.171.124).
- Plant LSMT protein-lysine methyltransferase. LSMT homologs from plants
display different substrate specificities, with targets involved in carbon
- [Cytochrome c]-lysine N-methyltransferase (EC 126.96.36.199).
The profiles we developed to identify Class V SAM-dependent methyltransferases
families are directed against whole length proteins.
PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and
distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives
(CC BY-NC-ND 4.0) License, see