What is the function of the Catechol-O-Methyltransferase (COMT) gene?

COMT Gene Function

The COMT (Catechol-O-Methyltransferase) gene encodes an enzyme that metabolizes and degrades catecholamines—specifically dopamine, epinephrine, and norepinephrine—by transferring a methyl group from S-adenosylmethionine to these neurotransmitters. 1, 2

Primary Enzymatic Function

• COMT catalyzes the methylation of catechol compounds, which results in the breakdown and inactivation of key neurotransmitters including dopamine, epinephrine, and norepinephrine 2, 3
• The enzyme transfers a methyl group from S-adenosylmethionine (SAM) to one of the catechol hydroxyl groups on the benzene ring of these neurotransmitters 3, 4
• This methylation process is a critical phase II metabolic pathway that regulates catecholamine levels throughout the body 3

Neurological and Physiological Impact

• COMT plays a crucial role in dopamine neurotransmission, which directly affects episodic memory encoding and retrieval through nerve cell signaling 1
• The enzyme is essential for maintaining proper levels of neurotransmitters involved in reward processing, motor control, motivation, and the "fight-or-flight" response 5, 6
• COMT activity directly influences cognitive and affective processes, including mood regulation and executive function 5

Genetic Variants and Clinical Significance

• Genetic variations in COMT alter enzyme activity levels, with the Val158Met polymorphism being the most clinically significant variant 1
• Met carriers have low enzyme activity, leading to slower catecholamine degradation and potentially higher dopamine levels in certain brain regions 1
• Val carriers have higher enzyme activity, resulting in faster catecholamine metabolism and lower dopamine availability 1

Disease Associations

• COMT metabolic disorders are implicated in multiple neurological and psychiatric conditions including Parkinson's disease, schizophrenia, obsessive-compulsive disorder, bipolar disorders, and treatment-resistant depression 5, 2, 3
• Associations between COMT gene variants and OCD have been reported, supporting the role of dopaminergic dysfunction in compulsive behaviors 5
• The Val allele specifically increases risk for cognitive impairment following certain treatments, such as chemotherapy-induced cognitive dysfunction 1

Pharmacological Relevance

• COMT serves as an important drug target, particularly in Parkinson's disease treatment where COMT inhibitors (tolcapone and entacapone) prevent dopamine breakdown 2
• COMT genetic variants affect how patients respond to medications involving catecholamine neurotransmitters, including SSRIs and other antidepressants 1
• The enzyme also metabolizes xenobiotic catechols from food and drugs, affecting pharmacokinetics and drug availability 3, 7

Clinical Testing Considerations

• Pharmacogenetic testing for COMT variants can identify patients who may experience altered metabolism of catecholamine-affecting drugs, those at higher risk for medication side effects, and individuals requiring dose adjustments 1
• Testing may be particularly relevant for patients with treatment-resistant depression, those experiencing unusual or severe side effects to standard doses, and patients with comorbid conditions affecting drug metabolism 1