COMT (catechol-O-methyltransferase; HGNC:2228, NCBI Gene ID 1312) is a human locus mapped to chromosome band 22q11.21 that encodes membrane-bound (MB-COMT, 271 aa) & soluble (S-COMT, 221 aa) catechol-O-methyltransferase (EC 2.1.1.6). COMT acts in prefrontal dopamine, norepinephrine, epinephrine & catechol-estrogen O-methylation, together with MAOA (Monoamine Oxidase A Gene), Dopamine, and Norepinephrine. Encodes catechol-O-methyltransferase, the primary enzyme clearing dopamine in the prefrontal cortex.
Val158Met polymorphism in prefrontal executive cognition & pain; target of entacapone/opicapone in Parkinson disease
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 6-exon gene located within the 22q11.21 DiGeorge/velocardiofacial microdeletion region, driven by two distinct promoters (P1 and P2) that generate a shorter cytoplasmic soluble isoform (S-COMT) in peripheral tissues and a 50-residue-longer membrane-bound isoform (MB-COMT) in brain neurons.
Cellular & Tissue Expression Profile: MB-COMT is highly expressed in postsynaptic pyramidal neurons and glia of the dorsolateral prefrontal cortex, where dopamine transporter (DAT / SLC6A3) expression is sparse, while S-COMT is abundant in hepatocytes, renal tubular epithelium, and erythrocytes.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Transfers a methyl group from S-adenosyl-L-methionine (SAM) to one of the phenolic hydroxyl groups of catecholamines (dopamine, norepinephrine, epinephrine, L-DOPA) in an Mg2+-dependent reaction, converting dopamine to 3-methoxytyramine (and homovanillic acid in concert with MAOA/MAOB) and degrading L-DOPA to 3-O-methyldopa.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: The widely studied functional coding polymorphism rs4680 (c.472G>A, p.Val158Met in MB-COMT) reduces enzyme thermostability and catalytic activity by 3- to 4-fold at physiological temperature, elevating tonic prefrontal cortical dopamine levels (enhancing working memory stability while increasing pain and stress sensitivity) and contributing to neuropsychiatric risk when hemizygously deleted in 22q11.2 deletion syndrome.
Therapeutic & Clinical Pharmacology: Nitrocatechol COMT inhibitors (the peripherally acting entacapone and opicapone, and tolcapone, which also inhibits COMT in the brain) are coadministered with levodopa/carbidopa in Parkinson disease to block peripheral O-methylation of L-DOPA and prolong striatal dopamine availability.