Reactome | Methylation

Methylation

Stable Identifier

R-HSA-156581

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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.

Literature References

PubMed ID	Title	Journal	Year
15130560	S-adenosylmethionine: nothing goes to waste Fontecave, M, Atta, M, Mulliez, E	Trends Biochem Sci	2004
10331075	Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase Weinshilboum, RM, Otterness, DM, Szumlanski, CL	Annu Rev Pharmacol Toxicol	1999
10898761	Changes in methionine adenosyltransferase and S-adenosylmethionine homeostasis in alcoholic rat liver Lu, SC, Huang, ZZ, Yang, H, Mato, JM, Avila, MA, Tsukamoto, H	Am J Physiol Gastrointest Liver Physiol	2000
	Casarett and Doull's Toxicology 5th Edn Parkinson, A		1995