PROSITE documentation PDOC51565
Class V SAM-dependent methyltransferases family profiles


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 (see <PDB:6ICT>) [4,5], enzymes belonging to this class N-methylate lysine in proteins. Most of them are histone methyltransferases (EC 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 in plants; in these enzymes the SET domain is interrupted by a novel domain [4]. Cytochrome c lysine N-methyltransferases (EC 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 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
  • Suvar4-20 histone-lysine N-methyltransferase (EC
  • SET2 histone-lysine N-methyltransferase (EC
  • PR/SET histone-lysine N-methyltransferase (EC
  • Suvar3-9 histone-lysine N-methyltransferase (EC
  • EZ histone-lysine N-methyltransferase (EC
  • SET7 histone-lysine N-methyltransferase (EC
  • 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

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

Last update:

October 2019 / Profile and text revised.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

SAM_MT127, PS51583; Plant LSMT protein-lysine methyltransferase family profile  (MATRIX)

SAM_MT43_1, PS51572; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_2, PS51574; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_3, PS51580; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_EZ, PS51576; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_PR_SET, PS51571; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SET2_1, PS51568; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SET2_2, PS51578; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SET7, PS51577; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SUVAR39_1, PS51573; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SUVAR39_2, PS51575; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SUVAR39_3, PS51579; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SUVAR420_1, PS51567; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_SUVAR420_2, PS51570; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT43_TRX_MLL, PS51566; Histone-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT59, PS51611; [Cytochrome c]-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT85_SETD3, PS51565; SETD3 actin-histidine N-methyltransferase (EC family profile  (MATRIX)


1AuthorsKozbial P.Z. Mushegian A.R.
TitleNatural history of S-adenosylmethionine-binding proteins.
SourceBMC Struct. Biol. 5:19-19(2005).
PubMed ID16225687

2AuthorsSchubert H.L. Blumenthal R.M. Cheng X.
TitleMany paths to methyltransfer: a chronicle of convergence.
SourceTrends. Biochem. Sci. 28:329-335(2003).
PubMed ID12826405

3AuthorsWlodarski T. Kutner J. Towpik J. Knizewski L. Rychlewski L. Kudlicki A. Rowicka M. Dziembowski A. Ginalski K.
TitleComprehensive structural and substrate specificity classification of the Saccharomyces cerevisiae methyltransferome.
SourcePLoS One. 6:E23168-E23168(2011).
PubMed ID21858014

4AuthorsWilkinson A.W. Diep J. Dai S. Liu S. Ooi Y.S. Song D. Li T.-M. Horton J.R. Zhang X. Liu C. Trivedi D.V. Ruppel K.M. Vilches-Moure J.G. Casey K.M. Mak J. Cowan T. Elias J.E. Nagamine C.M. Spudich J.A. Cheng X. Carette J.E. Gozani O.
TitleSETD3 is an actin histidine methyltransferase that prevents primary dystocia.
SourceNature 565:372-376(2019).
PubMed ID30626964

5AuthorsKwiatkowski S. Seliga A.K. Vertommen D. Terreri M. Ishikawa T. Grabowska I. Tiebe M. Teleman A.A. Jagielski A.K. Veiga-da-Cunha M. Drozak J.
TitleSETD3 protein is the actin-specific histidine N-methyltransferase.
SourceElife 7:0-0(2018).
PubMed ID30526847

6AuthorsYeates T.O.
TitleStructures of SET domain proteins: protein lysine methyltransferases make their mark.
SourceCell 111:5-7(2002).
PubMed ID12372294

7AuthorsPorras-Yakushi T.R. Whitelegge J.P. Clarke S.
TitleYeast ribosomal/cytochrome c SET domain methyltransferase subfamily: identification of Rpl23ab methylation sites and recognition motifs.
SourceJ. Biol. Chem. 282:12368-12376(2007).
PubMed ID17327221


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 prosite_license.html.


View entry in original PROSITE document format
View entry in raw text format (no links)