COMTs

COMTs, or catechol-O-methyltransferases, are enzymes that catalyze the transfer of a methyl group from S-adenosyl-L-methionine to catechol substrates, including dopamine, norepinephrine, epinephrine, and catechol estrogens. They participate in the inactivation and metabolism of catecholamines and related compounds across various tissues, with notable activity in the liver, kidney, and brain. In the brain, COMT contributes to the breakdown of dopamine, especially in areas such as the prefrontal cortex where dopamine transporter–mediated reuptake is relatively low, making COMT a key pathway for dopamine clearance in those regions.

Structure and genetics

The COMT gene is located on chromosome 22q11.21 and encodes two major protein isoforms through alternative translation: soluble COMT (S-COMT) and membrane-bound COMT (MB-COMT). These forms share catalytic properties but differ in subcellular localization, with MB-COMT associated with membranes and S-COMT found in the cytosol. A well-studied polymorphism, Val158Met (rs4680), alters enzymatic activity and thermal stability: the Val variant has higher activity than the Met variant. Other SNPs also influence expression and activity. The phenotypic effects of these variants can vary and are influenced by tissue context and environmental factors.

Clinical significance

COMT inhibitors such as entacapone, tolcapone, and opicapone are used alongside L-DOPA in Parkinson’s disease to reduce peripheral metabolism of L-DOPA and enhance central availability. Tolcapone carries a risk of hepatotoxicity, whereas entacapone is primarily peripheral in action and generally better tolerated; opicapone is a long-acting inhibitor. Beyond movement disorders, COMT participates in catechol estrogen metabolism, though the clinical implications of this role remain an area of research.