CatecholOmethyltransferase

Catechol-O-methyltransferase (COMT) is an enzyme that degrades catecholamines by transferring a methyl group from S-adenosyl-L-methionine (SAM) to the meta-hydroxyl group of catechol substrates, forming methylated metabolites such as metanephrine, normetanephrine, or related products. COMT acts on dopamine, norepinephrine, and epinephrine, contributing to their inactivation in both the brain and peripheral tissues, and it also metabolizes other catechol-containing compounds including catechol estrogens. The enzyme helps terminate catecholamine signaling and operates in conjunction with monoamine oxidase in a two-step pathway.

COMT exists in two main isoforms: a soluble cytosolic form (S-COMT) and a membrane-bound form (MB-COMT). Both arise from the COMT gene, which is located on chromosome 22q11.21 and can be expressed in multiple tissues, with MB-COMT enriched in neural and hepatic membranes. The two forms differ in cellular localization and kinetic properties, contributing to tissue-specific regulation of catecholamine metabolism.

Genetic variation influences COMT activity. The Val158Met polymorphism is the most studied variant, with the Val allele associated with higher enzymatic activity than the Met allele. This variation can affect dopaminergic signaling in the prefrontal cortex and has been linked to differences in cognitive function, pain sensitivity, and susceptibility to certain neuropsychiatric conditions.

Clinically, COMT inhibitors such as entacapone, tolcapone, and opicapone are used with L-DOPA therapy in Parkinson’s disease to extend central and peripheral dopamine availability by slowing its breakdown. Plasma or urinary metanephrine and normetanephrine measurements are used in screening for pheochromocytoma, reflecting COMT’s role in metabolizing circulating catecholamines.