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

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

3. 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 and
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.

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

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

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

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

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

9. Catechol O-methyl transferase Function

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

11. 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

12. 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

13. 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

14. 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)

15. COMT Mechanism

16. 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

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

18. 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