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discounted EARLY registration ends Dec 31, 2014
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Homo sapiens Enzyme: catechol O-methyltransferase

Gene: COMT Accession Number: HS01791 (HumanCyc)

Synonyms: MB-COMT

Summary:
The enzyme catalyzes the O-methylation and inactivation, of catecholamine neurotransmitters and catechol hormones. It also decreases the biological half-lives of neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol. Two alleles are responsible for a three to four-fold difference in enzymatic activity. Low enzyme activity alleles are associated with genetic susceptibility to alcoholism [MIM:103780].

The enzyme has soluble and membrane-bound isoforms. The soluble isoform is produced by alternative transcription initiation at a second promoter [Tenhunen94]. The subunit composition of human membrane-bound catechol O-methyltransferase has not been reported. The relative abundance of these two isoforms differs in different tissues. The highest activities are found in liver and kidney. It is also expressed in brain, placenta, lymphocytes and erthrocytes. The enzyme occurrs in animals, plants and microorganisms.

The molecular mass was determined by SDS-PAGE using recombinant enzyme from a Hep G2 cDNA clone transiently expressed in human embryonic kidney 293 cells [Bertocci91]. Recombinant enzyme has also been expressed in insect Sf9 cells using a baculovirus vector [Lotta95].

Citations: [Rivett82]

Locations: membrane

Map Position: [16,869,696 -> 16,896,850] (35.33 centisomes) on Chromosome 22
Length: 27155 bp

Molecular Weight of Polypeptide: 29 kD (experimental) [Bertocci91 ]

Unification Links: Ensembl:ENSG00000093010 , Entrez-gene:1312 , Entrez-Nucleotide:BC000419 , Entrez-Nucleotide:BC011935 , Entrez-Nucleotide:M58525 , Entrez-Nucleotide:M65212 , Entrez-Nucleotide:M65213 , Entrez-Nucleotide:Z26491 , GeneCards:COMT , MOPED:P21964 , OMIM:116790 , RefSeq:NM_000754 , RefSeq:NM_007310 , RefSeq:NP_000745 , RefSeq:NP_009294 , UCSC Human Genome:NM_000754 , UniGene:240013 , UniProt:P21964

Gene-Reaction Schematic: ?

Instance reactions of [a catechol + S-adenosyl-L-methionine → a guaiacol + S-adenosyl-L-homocysteine + H+] (2.1.1.6):
i1: 3,4-dihydroxyphenylglycol + S-adenosyl-L-methionine → 3-methoxy-4-hydroxyphenylglycol + S-adenosyl-L-homocysteine + H+ (2.1.1.6)

i2: 3,4-dihydroxymandelate + S-adenosyl-L-methionine → vanillyl mandelate + S-adenosyl-L-homocysteine + H+ (2.1.1.6)

i3: 3,4-dihydroxyphenylacetate + S-adenosyl-L-methionine → homovanillate + S-adenosyl-L-homocysteine + H+ (2.1.1.6)

i4: S-adenosyl-L-methionine + dopamine → S-adenosyl-L-homocysteine + 3-methoxytyramine + H+ (2.1.1.6)

i5: (R)-adrenaline + S-adenosyl-L-methionine → metanephrine + S-adenosyl-L-homocysteine + H+ (2.1.1.6)

i6: (R)-noradrenaline + S-adenosyl-L-methionine → normetanephrine + S-adenosyl-L-homocysteine + H+ (2.1.1.6)

i7: L-dopa + S-adenosyl-L-methionine → 3-O-methyldopa + S-adenosyl-L-homocysteine + H+ (2.1.1.6)

GO Terms:

Cellular Component: GO:0016020 - membrane [Jeffery84]


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

a catechol + S-adenosyl-L-methionine <=> a guaiacol + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: L-dopa degradation , dopamine degradation , noradrenaline and adrenaline degradation


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

(R)-noradrenaline + S-adenosyl-L-methionine <=> normetanephrine + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: noradrenaline and adrenaline degradation


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

(R)-adrenaline + S-adenosyl-L-methionine <=> metanephrine + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: noradrenaline and adrenaline degradation


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

L-dopa + S-adenosyl-L-methionine <=> 3-O-methyldopa + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: L-dopa degradation


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

3,4-dihydroxyphenylglycol + S-adenosyl-L-methionine <=> 3-methoxy-4-hydroxyphenylglycol + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: noradrenaline and adrenaline degradation


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

3,4-dihydroxymandelate + S-adenosyl-L-methionine <=> vanillyl mandelate + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: noradrenaline and adrenaline degradation


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

3,4-dihydroxyphenylacetate + S-adenosyl-L-methionine <=> homovanillate + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: dopamine degradation


Enzymatic reaction of: catechol O-methyltransferase (catechol O-methyltransferase)

EC Number: 2.1.1.6

S-adenosyl-L-methionine + dopamine <=> S-adenosyl-L-homocysteine + 3-methoxytyramine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

Alternative Substrates for dopamine: (R)-noradrenaline [Lotta95 ] , L-dopa [Lotta95 ] , protocatechuate [Lotta95 ]

In Pathways: dopamine degradation

Summary:
Catechol O-methyltransferase catalyzes the transfer of the methyl group from S-adenosyl-L-methionine to one of the hydroxyl groups of a catechol, in the presence of Mg2+. Its physiological function is to inactivate biologically active, or toxic catechols. The membrane-bound isoform has lower Km values for catechol substrates than the soluble form. The Km for dopamine was approximately 100-fold lower for the membrane-bound form than the soluble form. The ratio of the products 3-methoxytyramine to 4-methoxytyramine was 8.8. The enzyme showed both substrate and product inhibition. Triton X-100 inhibited the membrane-bound, but not the soluble form of the enzyme. [Rivett82, Jeffery84, Bertocci91, Lotta95].

Activators (Unknown Mechanism): Mg2+ [Rivett82]

Inhibitors (Competitive): nitecapone [Lotta95] , entacapone [Lotta95] , tolcapone [Lotta95, Bertocci91] , nordihydroguaiaretate [Jeffery84] , tropolone [Bertocci91, Jeffery84, Rivett82] , S-adenosyl-L-homocysteine [Rivett82]

Inhibitors (Other): 3-methoxytyramine [Rivett82]

Inhibitors (Unknown Mechanism): Ca2+ [Jeffery84]

Kinetic Parameters:

Substrate
Km (μM)
Citations
dopamine
3.3
[Rivett82]
S-adenosyl-L-methionine
3.1
[Rivett82]

pH(opt): 7.0-7.6 [Rivett82]


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

(R)-noradrenaline + S-adenosyl-L-methionine <=> normetanephrine + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: noradrenaline and adrenaline degradation

Summary:
Human recombinant membrane-bound and and soluble forms of the enzyme were exressed in Escherichia coli, purified and characterized kinetically using a variety of different substrates [Bai07].

Kinetic Parameters:

Substrate
Km (μM)
Citations
(R)-noradrenaline
29.6
[Bai07]


Enzymatic reaction of: catechol O-methyltransferase

EC Number: 2.1.1.6

(R)-adrenaline + S-adenosyl-L-methionine <=> metanephrine + S-adenosyl-L-homocysteine + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is physiologically favored in the direction shown.

In Pathways: noradrenaline and adrenaline degradation

Summary:
Please see the summary for noradrenaline O-methyltransferase activity, below.

Kinetic Parameters:

Substrate
Km (μM)
Citations
(R)-adrenaline
27.9
[Bai07]


Gene Local Context (not to scale): ?

Exons/Introns:


References

Bai07: Bai HW, Shim JY, Yu J, Zhu BT (2007). "Biochemical and molecular modeling studies of the O-methylation of various endogenous and exogenous catechol substrates catalyzed by recombinant human soluble and membrane-bound catechol-O-methyltransferases." Chem Res Toxicol 20(10);1409-25. PMID: 17880176

Bertocci91: Bertocci B, Miggiano V, Da Prada M, Dembic Z, Lahm HW, Malherbe P (1991). "Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form." Proc Natl Acad Sci U S A 88(4);1416-20. PMID: 1847521

Jeffery84: Jeffery DR, Roth JA (1984). "Characterization of membrane-bound and soluble catechol-O-methyltransferase from human frontal cortex." J Neurochem 42(3);826-32. PMID: 6693904

Lotta95: Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995). "Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme." Biochemistry 34(13);4202-10. PMID: 7703232

Rivett82: Rivett AJ, Roth JA (1982). "Kinetic studies on the O-methylation of dopamine by human brain membrane-bound catechol O-methyltransferase." Biochemistry 21(8);1740-2. PMID: 7082642

Tenhunen94: Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, Savolainen R, Ulmanen I (1994). "Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters." Eur J Biochem 223(3);1049-59. PMID: 8055944


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of HumanCyc: Genome Biology 6(1):1-17 2004
Page generated by SRI International Pathway Tools version 18.5 on Sat Nov 22, 2014, BIOCYC13B.