PathwayStep2729 PathwayStep2728 PathwayStep2730 PathwayStep2732 PathwayStep2731 PathwayStep2584 PathwayStep2583 PathwayStep2582 Methylation Authored: Jassal, B, 2005-02-03 14:13:47 Edited: Jassal, B, 2008-05-19 12:57:01 GENE ONTOLOGYGO:0032259 Methylation is a common but minor pathway of Phase II conjugation compared to glucuronidation or sulfonation. The cofactor used in methylation conjugation is S-adenosylmethionine (SAM). SAM is the second most widely used enzyme substrate after ATP and is involved in a wide range of important biological processes. SAM is sythesized from methionine's reaction with ATP, catalyzed by methionine adenosyltransferase (MAT). There are two genes, MAT1A and MAT2A, which encode for two homologous MAT catalytic subunits, 1 and 2. During conjugation with nucleophilic substrates, the methyl group attached to the sulfonium ion of SAM is transferred to the substrate forming the conjugate. SAM, having lost the methyl moiety, is converted to S-adenosylhomocysteine (SAH). SAH can be hydrolyzed to form adenosine and homocysteine. Homocysteine can either be converted to glutathione or methylated to form methionine, thus forming the starting point for SAM synthesis and completing the cycle. Fuctional groups attacked are phenols, catechols, aliphatic and aromatic amines and sulfhydryl-containing groups. The enzymes that catalyze the transfer of the methyl group to these functional groups are the methyltransferases (MT). MTs are small, cytosolic, monomeric enzymes that utilize SAM as a methyl donor. There are many MTs but the best studied ones are named on the basis of their prototypical substrates: COMT (catechol O-methyltransferase), TPMT (thiopurine methyltransferase), TMT (thiol methyltransferase), HNMT (histamine N-methyltransferase) and NNMT (nicotinamide N-methyltransferase). An example of each enzyme mentioned is given. In each case, a typical substrate for the enzyme is shown. Pubmed10331075 Pubmed10898761 Pubmed15130560 Reactome Database ID Release 43156581 Reactome, http://www.reactome.org ReactomeREACT_6946 Methionine is reformed SAM is sythesized from methionine's reaction with ATP S-adenoylhomocysteine is hydrolyzed Pyridine can be N-methylated 3,4-dihydroxybenzoate can be O-methylated 6-mercaptopurine can be S-methylated 2-mercaptoethanol can be S-methylated S-atom dealkylation of 6-methylmercaptopurine