Catechol O-methyltransferase Structure/Overview: Hillary Vaughan Function/Role: Sterling Scaggs

Overview: enzyme encoded by the COMT gene degrades catecholamines pharmaceutical target Julius Axelrod 1957 Epinephrine Norepinephrine

COMT Gene: location: chromosome 22 size: 28,369 b.p.’s Two versions: MB-COMT and S-COMT allelic variant: Val158Met The COMT gene is located on the long (q) arm of chromosome 22 between positions 11.21 and 11.23. More precisely, the COMT gene is located from base pair 19,929,262 to base pair 19,957,497 on chromosome 22. The longer form, called membrane-bound catechol-O-methyltransferase (MB-COMT), is chiefly produced by nerve cells in the brain. Other tissues, including the liver, kidneys, and blood, produce a shorter form of the enzyme called soluble catechol-O-methyltransferase (S-COMT). This form of the enzyme helps control the levels of certain hormones. particularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behaviors, abstract thinking, emotion, and working (short-term) memory. To function efficiently, the prefrontal cortex requires signalling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain. In genetics, rs4680 (Val158Met) is a genetic variant. It is a single nucleotide polymorphism (SNP) in the COMT gene that codes catechol-O-Methyltransferase. The single nucleotide substitution between G--> A results in an amino acid change from valine to methionine at codon 158. The A or Met allele is associated with lower enzymatic activity (due to thermoinstability), and with exploratory behaviour.

Protein Structure: 221 Amino Acids 8 α helices 7 β strands “Rossmann Fold” motif Mg2+ ion co-enzyme: SAM

Conserved Sequences: Gly66 β1→α4 Rat 81% identical to human Arg 38 in pig is Trp 38 in humans/rats

Consensus Regions: COMT and other mammalian methyltransferases region a: binding of SAM coenzyme

SAM: S-Adenosyl methionine coenzyme SAM binds to COMT COMT must be complexed with Mg2+

The Active Site Mg2+ has catalytic activity 3,5-dinitrocatechol inhibitor hydrogen bonds and hydrophobic effect

Catechol O-methyl transferase Function

Inactivation Catecholamine are molecules that have a catechol nucleus Catecholamine neurotransmitters Dopamine Epinephrine Norepinephrine

Dopamine Activates the five known types of dopamine receptors; D1, D2, D3, D4, and D5 Main function: inhibit the release of prolactin from the anterior lobe of the pituitary

Epinephrine Referred to as Adrenaline Increases heart rate, constricts blood vessels, dilates air passages Participates in the fight-or-flight response of the sympathetic nervous system Produced only by the adrenal glands from the amino acids phenylalanine and tyrosine

Norepinephrine Released from the sympathetic neurons affecting the heart Increases the rate of contractions Suppresses neuroinflammation when released diffusely in the brain from the locus coeruleus As a drug it increases blood pressure by increasing vascular tone

COMT The COMT gene provides instructions for making an enzyme called Catechol-O-methyltransferase. Two versions of the enzyme are formed, membrane-bound catechol-O-methyltransferase (MB-COMT) & soluble catechol-O- methyltransferase (S-COMT)

COMT Mechanism

MB-COMT This is the longer form of the enzyme Chiefly produced by nerve cells in the brain MB-COMT can inactivate synaptic and extrasynaptic dopamine on the surface of presynaptic and postsynaptic neurons

S-COMT The liver, kidneys, and blood, produce S-COMT This is the shorter form of the enzyme S-COMT is activated and unmethylated

Role of COMT Helps break down certain chemical messengers called neurotransmitters Transmit signals from one nerve cell to another Important in an area at the front of the brain called the prefrontal cortex