InterPro domain: IPR010280

This family consists of (uracil-5-)-methyltransferases 2.1.1.35 from bacteria, archaea and eukaryotes. They are class I-like SAM-binding methyltransferases.

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, signaltransduction, 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. A review published in 2003 [ 4 ] divides all MTs into 5 classes based on the structure of their catalytic domain (fold):

• class I: Rossmann-like alpha/beta
• class II: TIM beta/alpha-barrel alpha/beta
• class III: tetrapyrrole methylase alpha/beta
• class IV: SPOUT alpha/beta
• class V: SET domain all beta

A more recent paper [ 4 ] based on a study of the Saccharomyces cerevisiae methyltransferome argues for four more folds:

• class VI: transmembrane all alpha
• class VII: DNA/RNA-binding 3-helical bundle all alpha
• class VIII: SSo0622-like alpha+beta
• class IX: thymidylate synthetase alpha+beta

The vast majority of MTs belong to the Rossmann-like fold (Class I) whichconsists in a seven-stranded beta sheet adjoined by alpha helices. The betasheet contains a central topological switch-point resulting in a deep cleft inwhich SAM binds. Class I MTs display two conserved positions, the first one isa GxGxG motif (or at least a GxG motif) at the end of the first beta strandwhich is characteristic of a nucleotide-binding site and is hence used to bindthe adenosyl part of SAM, the second conserved position is an acidic residueat the end of the second beta strand that forms one hydrogen bond to eachhydroxyl of the SAM ribose part. The core of these enzymes is composed byabout 150 amino acids that show very strong spatial conservation. Catechol O-MT (EC 2.1.1.6) is the canonical Class I MT considering that it consists inthe exact consensus structural core with no extra domain [ 4 ].

1. Natural history of S-adenosylmethionine-binding proteins. BMC Struct. Biol. 5, 19
2. Many paths to methyltransfer: a chronicle of convergence. Trends Biochem. Sci. 28, 329-35
3. Comprehensive structural and substrate specificity classification of the Saccharomyces cerevisiae methyltransferome. PLoS ONE 6, e23168