catechol-O-methyltransferase

**Function and biochemistry** - COMT catalyzes O-methylation of catechols (a benzene ring with two adjacent hydroxyl groups). The methyl donor is S-adenosylmethionine (SAM), which becomes S-adenosylhomocysteine. Mg2+ is a cofactor. - Substrates: dopamine, norepinephrine, epinephrine, levodopa, and catechol estrogens (2-hydroxyestradiol). - Location: found in the liver, kidney, and other peripheral tissues, and in the brain, including the prefrontal cortex. It is cytosolic (soluble form) and membrane-bound (MB-COMT). The adrenal medulla also expresses it. - Key point: COMT acts mainly on catecholamines outside the neuron (synaptic cleft, glia, and peripheral tissue). MAO acts mainly inside the presynaptic terminal on the mitochondrial outer membrane. Reuptake (NET/DAT) is the main way synaptic catecholamine action ends.

**Catecholamine metabolism (high-yield pathway)** - Epinephrine → (COMT) → metanephrine → (MAO) → vanillylmandelic acid (VMA) - Norepinephrine → (COMT) → normetanephrine → (MAO) → VMA - Dopamine → (COMT) → 3-methoxytyramine → (MAO) → homovanillic acid (HVA) - Dopamine → (MAO) → DOPAC → (COMT) → HVA - Levodopa → (COMT) → 3-O-methyldopa. This is a peripheral metabolite that competes with levodopa for transport across the blood-brain barrier. - Phenylethanolamine-N-methyltransferase (PNMT) is a different enzyme. It converts norepinephrine to epinephrine in the adrenal medulla and is induced by cortisol. It also uses SAM, so don't confuse it with COMT.

**Clinical significance** 1. **Parkinson disease** - Levodopa is given with carbidopa, a peripheral DOPA decarboxylase inhibitor. Carbidopa blocks decarboxylation, so more of the dose goes through COMT, producing 3-O-methyldopa. - COMT inhibitors block this pathway, which raises levodopa bioavailability and prolongs its half-life. They reduce motor fluctuations ("wearing-off" or end-of-dose phenomenon). - Entacapone and opicapone act peripherally. Tolcapone acts peripherally and centrally, but it carries a risk of hepatotoxicity (fulminant liver failure), so it needs LFT monitoring and is reserved for patients who don't respond to other agents. - Side effects: dyskinesias (from increased dopaminergic stimulation), nausea, orthostatic hypotension, and diarrhea. Entacapone and tolcapone can cause brownish-orange urine discoloration. Tolcapone is also associated with diarrhea. 2. **Pheochromocytoma and paraganglioma** - Tumors make catecholamines, and COMT converts them to metanephrines inside tumor cells. This happens continuously, independent of episodic catecholamine release. - Plasma free metanephrines or 24-hour urinary fractionated metanephrines are the best screening tests (high sensitivity). Urinary VMA and catecholamines are less sensitive. 3. **Genetic polymorphism (Val158Met, rs4680)** - A G→A substitution causes valine to methionine at codon 158. The Met allele makes a thermolabile enzyme with 3–4 times lower activity. This means higher prefrontal dopamine. - Associations studied: executive function and working memory, anxiety, pain sensitivity, and schizophrenia risk. The "warrior (Val) versus worrier (Met)" idea is a popular simplification, and evidence is mixed. - The 22q11.2 deletion syndrome (DiGeorge/velocardiofacial) deletes the COMT gene, and this is linked to a higher risk of schizophrenia and psychiatric disease. 4. **Estrogen metabolism** - COMT inactivates catechol estrogens, which may be genotoxic. Lower activity has been studied as a possible factor in breast cancer risk, but the evidence is inconsistent. 5. **Drug interactions** - COMT inhibitors can increase levels of other catechol-containing drugs, for example methyldopa, dobutamine, isoproterenol, and epinephrine. Take caution with these combinations. - Combining COMT inhibitors with nonselective MAO inhibitors is contraindicated because both main catecholamine degradation pathways are blocked. Selective MAO-B inhibitors (selegiline, rasagiline) are acceptable.

**Board pearls** - COMT and MAO are both needed to produce VMA and HVA. - COMT is SAM-dependent. SAM is made from methionine and ATP. - Entacapone and tolcapone → Parkinson adjunct (they prevent levodopa breakdown). Tolcapone → liver toxicity. - Metanephrines = best screening test for pheochromocytoma. The classic triad is episodic headache, sweating, and palpitations, along with hypertension. Treat with an alpha-blocker (phenoxybenzamine) first, then a beta-blocker, then surgery.