Catechol-O-methyltransferase (COMT) is one of several enzymes that degrade catecholamines (such as dopamine, epinephrine, and norepinephrine) and various substances having a catechol structure. COMT inhibitors such as entacapone, tolcapone and opicapone are used in the treatment of Parkinson's disease.

Dihydroxybenzoate is a typical substrate for Catechol O-methyltransferase

Dopamine (DA) in the cytosol is methylated to 3-methoxytyramine (3MT) by catecholamine O-methyltransferase (COMT), which uses s-adenosylmethionine (AdoMet) as a methyl group donor (Männistö & Kaakkola 1991, Westerink & Spaan 1989).

3,4-dihydroxyphenylacetic acid (DOPAC), generated after oxidative deamination of dopamine by monoamine oxidase A (MAOA), is methylated by catecholamine O-methyltransferase (COMT) to homovanillic acid (HVA) (Deeds et al.1957).

The human gene SLC6A3 encodes the sodium-dependent dopamine transporter, DAT which mediates the re-uptake of dopamine from the synaptic cleft (Vandenbergh DJ et al, 2000). Dopamine can then be degraded by either COMT or monoamine oxidase.

Dopamine once taken up by the dopamine transporter from the extracellular space into the cytosol is metabolized in a two step reaction to homovanillic acid.The first reaction is catalyzed by catecholamine o-methyl transferase and the subsequent reaction is catalyzed by monoamine oxidase A.

The human gene SLC6A3 encodes the sodium-dependent dopamine transporter, DAT which mediates the re-uptake of dopamine from the synaptic cleft (Vandenbergh DJ et al, 2000). Dopamine can then be degraded by either COMT or monoamine oxidase.

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.