PROSITE documentation PDOC51555
Class I SAM-dependent methyltransferases family profiles


Methyltransferases (MTs) (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. MTs 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 MTs 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 MTs into 5 classes based on the structure of their catalytic domain (fold):

  • class I: Rossmann-like α/β
  • 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 see <PDOC51565>

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

The vast majority of MTs belong to the Rossmann-like fold (Class I) which consists in a seven-stranded β sheet adjoined by α helices. The β sheet contains a central topological switch-point resulting in a deep cleft in which SAM binds. Class I MTs display two conserved positions, the first one is a GxGxG motif (or at least a GxG motif) at the end of the first β strand which is characteristic of a nucleotide-binding site and is hence used to bind the adenosyl part of SAM, the second conserved position is an acidic residue at the end of the second β strand that forms one hydrogen bond to each hydroxyl of the SAM ribose part. The core of these enzymes is composed by about 150 amino acids that show very strong spatial conservation. Catechol O-MT (EC is the canonical Class I MT considering that it consists in the exact consensus structural core with no extra domain (see <PDB:1VID>) [2].

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

Profiles directed against domains:

  • C5-MTs (see <PDOC00089>): DNA (cytosine-5-)-MT (EC and tRNA (cytosine(38)-C(5))-MT (EC
  • Domains rearranged MTs (DRMs) (EC=
  • Dot 1 MT (EC (see <PDOC51569>).
  • Eukaryotic and dsDNA viruses mRNA cap 0 MT (EC (see <PDOC51562>).
  • Flavivirus mRNA cap 0 and cap 1 MT (EC and EC [4,5,6].
  • Mononegavirus L protein 2'-O-ribose MT domain, involved in the capping of viral mRNAs (cap 1 structure) [7,8].
  • Protein arginine N-MTs (PRMTs) including histone-arginine N-MT (EC and [Myelin basic protein]-arginine N-MT (EC
  • RMT2 MTs: arginine N-MT 2 (EC 2.1.1.-) and guanidinoacetate N-MT (EC [9,10].
  • TRM1 tRNA (guanine(26)-N(2))-diMT (EC
  • TRM5/TYW2 tRNA (guanine(37)-N(1))-MT (EC
  • ERG6/SMT MTs: methylate sterol and triterpene.
  • RsmB/NOP MTs: RNA (cytosine-5-)-MTs.
  • RNA 5-methyluridine (m(5)U) MTs (EC, EC and EC
  • RrmJ mRNA (nucleoside-2'-O-)-MT (EC
  • Adrift ribose 2'-O-MT (EC 2.1.1.-).
  • TrmB tRNA (guanine(46)-N(7))-MT (EC

Profiles directed against whole-length proteins:

  • Glycine and glycine/sarcosine N-methyltransferase (EC and EC
  • mRNA (2'-O-methyladenosine-N(6)-)-MT (EC and other MT-A70-like MTs.
  • Phosphoethanolamine N-MT (PEAMT) (EC
  • dsRNA viruses mRNA cap 0 MT (EC
  • Poxvirus/kinetoplastid cap ribose 2'-O-MT.
  • NNT1 nicotinamide N-MT (EC
  • NNMT/PNMT/TEMT MTs (see <PDOC00844>): nicotinamide N-MT (EC, phenylethanolamine N-MT (EC and amine N-MT (EC
  • HNMT histamine N-MT (EC
  • Putrescine N-MT (EC
  • CLNMT calmodulin-lysine N-MT (EC
  • TRM61 tRNA (adenine(57)-N(1)/adenine(58)-N(1) or adenine(58)-N(1))-MT (EC or EC
  • UbiE 2-methoxy-6-polyprenyl-1,4-benzoquinol methylase (EC
  • Tocopherol O-MT (EC The Synechocystis homologue has not a tocopherol MT but a MPBQ/MSBQ activity (EC (see below) [11,12].
  • 2-methyl-6-phytyl-1,4-benzoquinone/2-methyl-6-solanyl-1,4-benzoquinone MT (MPBQ/MSBQ MT) (EC [12].
  • Cation-dependent O-MT includes caffeoyl-CoA O-MT (CCoAOMT) (EC that is involved in plant defense, catechol O-MT (COMT) (EC that plays an important role in the central nervous system in the mammalian organism, and a family of bacterial OMTs that may be involved in antibiotic production.
  • Cation-independent O-MT includes caffeic acid OMTs that are able to methylate the monolignol precursors caffeic acid (EC, caffeyl aldehyde, or caffeyl alcohol, acetylserotonin OMT (EC and acetylserotonin OMT-like (EC 2.1.1.-).
  • Magnesium protoporphyrin IX MT (EC
  • rRNA adenine N(6)-MT and adenine N(6), N(6)-diMT.
  • TRM11 MTs: tRNA (guanine(10)-N2)-MT (EC and homologs (EC 2.1.1.-).
  • Methionine S-MT (EC
  • TPMT MTs: thiopurine S-MT (EC, thiol S-MT (EC and thiocyanate MT (EC 2.1.1.n4).

The profiles we developed cover the entire domains or families.

Last update:

October 2013 / Profile added and text revised.


Technical section

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

RNA_CAP01_NS5_MT, PS51591; mRNA cap 0 and cap 1 methyltransferase (EC and EC domain profile  (MATRIX)

SAM_CLNMT, PS51610; Calmodulin-lysine N-methyltransferase (EC family profile  (MATRIX)

SAM_GNMT, PS51600; Glycine N-methyltransferase (EC and EC family profile  (MATRIX)

SAM_GTMT, PS51581; SAM-dependent methyltransferase gamma-tocopherol (gTMT)-type family profile  (MATRIX)

SAM_HNMT, PS51597; Histamine N-methyltransferase (EC family profile  (MATRIX)

SAM_MPBQ_MSBQ_MT, PS51734; MPBQ/MBSQ family SAM-binding methyltransferase profile  (MATRIX)

SAM_MT12, PS51555; Methionine S-methyltransferase (EC family profile  (MATRIX)

SAM_MT56_VP3, PS51589; Viral protein 3 containing mRNA (guanine-N(7)-)-methyltransferase family profile  (MATRIX)

SAM_MTA70L_1, PS51563; mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase (EC family profile  (MATRIX)

SAM_MTA70L_2, PS51592; mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase-like (MT-A70-like) family profile  (MATRIX)

SAM_MT_2O_PK, PS51612; Poxvirus/kinetoplastid-type ribose 2'-O-methyltransferase (EC family profile  (MATRIX)

SAM_MT_ADRIFT, PS51614; Adrift-type ribose 2'-O-methyltransferase (EC 2.1.1.-) domain profile  (MATRIX)

SAM_MT_C5, PS51679; C-5 cytosine-specific DNA methylase (Dnmt) domain profile  (MATRIX)

SAM_MT_DRM, PS51680; SAM-dependent methyltransferase DRM-type domain profile  (MATRIX)

SAM_MT_ERG6_SMT, PS51685; SAM-dependent methyltransferase Erg6/SMT-type domain profile  (MATRIX)

SAM_MT_MG_PIX, PS51556; Magnesium protoporphyrin IX methyltransferase (EC family profile  (MATRIX)

SAM_MT_MNV_L, PS51590; Mononegavirus L protein 2'-O-ribose methyltransferase domain profile  (MATRIX)

SAM_MT_NNMT_PNMT_TEMT, PS51681; SAM-dependent methyltransferase NNMT/PNMT/TEMT-type profile  (MATRIX)

SAM_MT_NNT1, PS51560; Nicotinamide N-methyltransferase (EC family profile  (MATRIX)

SAM_MT_PRMT, PS51678; SAM-dependent methyltransferase PRMT-type domain profile  (MATRIX)

SAM_MT_PUTRESCINE, PS51615; Putrescine N-methyltransferase (EC family profile  (MATRIX)

SAM_MT_RNA_M5U, PS51687; SAM-dependent methyltransferase RNA m(5)U-type domain profile  (MATRIX)

SAM_MT_RRMJ, PS51613; RrmJ-type ribose 2'-O-methyltransferase (EC domain profile  (MATRIX)

SAM_MT_RSMB_NOP, PS51686; SAM-dependent MTase RsmB/NOP-type domain profile  (MATRIX)

SAM_MT_TPMT, PS51585; Thiopurine or thiol or thiocyanate S-methyltransferase (TPMT) family profile  (MATRIX)

SAM_MT_TRM1, PS51626; Trm1 methyltransferase domain profile  (MATRIX)

SAM_MT_TRM11, PS51627; tRNA methyltransferase 11 (TRM11) (EC 2.1.1.-) family profile  (MATRIX)

SAM_MT_TRM5_TYW2, PS51684; SAM-dependent methyltransferase TRM5/TYW2-type domain profile  (MATRIX)

SAM_MT_TRMB, PS51625; SAM-dependent methyltransferase TRMB-type domain profile  (MATRIX)

SAM_MT_UBIE, PS51608; UbiE family SAM-binding methyltransferase profile  (MATRIX)

SAM_OMT_I, PS51682; SAM-dependent O-methyltransferase class I-type profile  (MATRIX)

SAM_OMT_II, PS51683; SAM-dependent O-methyltransferase class II-type profile  (MATRIX)

SAM_PEAMT, PS51582; Phosphoethanolamine N-methyltransferase (PEAMT) (EC family profile  (MATRIX)

SAM_RMT2, PS51559; Arginine and arginine-like N-methyltransferase domain profile  (MATRIX)

SAM_RNA_A_N6_MT, PS51689; rRNA adenine N(6)-methyltransferase family profile  (MATRIX)

SAM_TRM61, PS51620; tRNA (adenine(57)-N(1)/adenine(58)-N(1) or adenine(58)-N(1)) (EC or 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

4AuthorsEgloff M.P. Benarroch D. Selisko B. Romette J.L. Canard B.
TitleAn RNA cap (nucleoside-2'-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization.
SourceEMBO J. 21:2757-2768(2002).
PubMed ID12032088

5AuthorsZhou Y. Ray D. Zhao Y. Dong H. Ren S. Li Z. Guo Y. Bernard K.A. Shi P.Y. Li H.
TitleStructure and function of flavivirus NS5 methyltransferase.
SourceJ. Virol. 81:3891-3903(2007).
PubMed ID17267492

6AuthorsGeiss B.J. Thompson A.A. Andrews A.J. Sons R.L. Gari H.H. Keenan S.M. Peersen O.B.
TitleAnalysis of flavivirus NS5 methyltransferase cap binding.
SourceJ. Mol. Biol. 385:1643-1654(2009).
PubMed ID19101564

7AuthorsBujnicki J.M. Rychlewski L.
TitleIn silico identification, structure prediction and phylogenetic analysis of the 2'-O-ribose (cap 1) methyltransferase domain in the large structural protein of ssRNA negative-strand viruses.
SourceProtein Eng. 15:101-108(2002).
PubMed ID11917146

8AuthorsFerron F. Longhi S. Henrissat B. Canard B.
TitleViral RNA-polymerases -- a predicted 2'-O-ribose methyltransferase domain shared by all Mononegavirales.
SourceTrends Biochem. Sci. 27:222-224(2002).
PubMed ID12076527

9AuthorsKomoto J. Yamada T. Takata Y. Konishi K. Ogawa H. Gomi T. Fujioka M. Takusagawa F.
TitleCatalytic mechanism of guanidinoacetate methyltransferase: crystal structures of guanidinoacetate methyltransferase ternary complexes.
SourceBiochemistry 43:14385-14394(2004).
PubMed ID15533043

10AuthorsKomoto J. Huang Y. Takata Y. Yamada T. Konishi K. Ogawa H. Gomi T. Fujioka M. Takusagawa F.
TitleCrystal structure of guanidinoacetate methyltransferase from rat liver: a model structure of protein arginine methyltransferase.
SourceJ. Mol. Biol. 320:223-235(2002).
PubMed ID12079381

11AuthorsEndrigkeit J. Wang X. Cai D. Zhang C. Long Y. Meng J. Jung C.
TitleGenetic mapping, cloning, and functional characterization of the BnaX.VTE4 gene encoding a gamma-tocopherol methyltransferase from oilseed rape.
SourceTheor. Appl. Genet. 119:567-575(2009).
PubMed ID19479236

12AuthorsCheng Z. Sattler S. Maeda H. Sakuragi Y. Bryant D.A. DellaPenna D.
TitleHighly divergent methyltransferases catalyze a conserved reaction in tocopherol and plastoquinone synthesis in cyanobacteria and photosynthetic eukaryotes.
SourcePlant Cell 15:2343-2356(2003).
PubMed ID14508009


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