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Protein

Catechol O-methyltransferase

Gene

COMT

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.

Catalytic activityi

S-adenosyl-L-methionine + a catechol = S-adenosyl-L-homocysteine + a guaiacol.

Cofactori

Mg2+Note: Binds 1 Mg2+ ion per subunit.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei92S-adenosyl-L-methionine; via amide nitrogenPROSITE-ProRule annotation1 Publication1
Binding sitei114S-adenosyl-L-methioninePROSITE-ProRule annotation1
Binding sitei122S-adenosyl-L-methioninePROSITE-ProRule annotation1 Publication1
Binding sitei140S-adenosyl-L-methioninePROSITE-ProRule annotation1 Publication1
Binding sitei141S-adenosyl-L-methionine; via amide nitrogenPROSITE-ProRule annotation1
Binding sitei169S-adenosyl-L-methionine; via amide nitrogenPROSITE-ProRule annotation1
Metal bindingi191Magnesium1 Publication1
Binding sitei191S-adenosyl-L-methioninePROSITE-ProRule annotation1 Publication1
Binding sitei194Substrate1
Metal bindingi219Magnesium1 Publication1
Metal bindingi220Magnesium1 Publication1
Binding sitei220Substrate1
Binding sitei249Substrate1

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Methyltransferase, Transferase

Keywords - Biological processi

Catecholamine metabolism, Neurotransmitter degradation

Keywords - Ligandi

Magnesium, Metal-binding, S-adenosyl-L-methionine

Enzyme and pathway databases

BioCyciMetaCyc:HS01791-MONOMER.
ZFISH:HS01791-MONOMER.
BRENDAi2.1.1.6. 2681.
ReactomeiR-HSA-156581. Methylation.
R-HSA-379397. Enzymatic degradation of dopamine by COMT.
R-HSA-379398. Enzymatic degradation of Dopamine by monoamine oxidase.

Names & Taxonomyi

Protein namesi
Recommended name:
Catechol O-methyltransferase (EC:2.1.1.6)
Gene namesi
Name:COMT
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 22

Organism-specific databases

HGNCiHGNC:2228. COMT.

Subcellular locationi

Isoform Membrane-bound :

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 6CytoplasmicSequence analysis6
Transmembranei7 – 26Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST20
Topological domaini27 – 271ExtracellularSequence analysisAdd BLAST245

GO - Cellular componenti

  • axon Source: Ensembl
  • cell body Source: Ensembl
  • cytosol Source: Reactome
  • dendritic spine Source: Ensembl
  • extracellular exosome Source: UniProtKB
  • integral component of membrane Source: UniProtKB-KW
  • membrane Source: UniProtKB
  • mitochondrion Source: Ensembl
  • plasma membrane Source: Reactome
  • postsynaptic membrane Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi1312.
MalaCardsiCOMT.
MIMi103780. phenotype.
116790. gene+phenotype.
OpenTargetsiENSG00000093010.
Orphaneti567. 22q11.2 deletion syndrome.
240863. Cisplatin toxicity.
3140. Schizophrenia.
PharmGKBiPA117.

Chemistry databases

ChEMBLiCHEMBL2023.
DrugBankiDB00286. Conjugated Estrogens.
DB00255. Diethylstilbestrol.
DB00841. Dobutamine.
DB00988. Dopamine.
DB00494. Entacapone.
DB00968. Methyldopa.
DB01141. Micafungin.
DB00118. S-Adenosylmethionine.
DB01420. Testosterone Propionate.
DB00323. Tolcapone.
GuidetoPHARMACOLOGYi2472.

Polymorphism and mutation databases

BioMutaiCOMT.
DMDMi116907.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000209711 – 271Catechol O-methyltransferaseAdd BLAST271

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei267PhosphoserineBy similarity1

Post-translational modificationi

The N-terminus is blocked.

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP21964.
MaxQBiP21964.
PaxDbiP21964.
PeptideAtlasiP21964.
PRIDEiP21964.
TopDownProteomicsiP21964-1. [P21964-1]
P21964-2. [P21964-2]

2D gel databases

REPRODUCTION-2DPAGEIPI00375513.

PTM databases

iPTMnetiP21964.
PhosphoSitePlusiP21964.
SwissPalmiP21964.

Expressioni

Tissue specificityi

Brain, liver, placenta, lymphocytes and erythrocytes.

Gene expression databases

BgeeiENSG00000093010.
CleanExiHS_COMT.
ExpressionAtlasiP21964. baseline and differential.
GenevisibleiP21964. HS.

Organism-specific databases

HPAiCAB011233.
HPA001169.

Interactioni

Binary interactionsi

WithEntry#Exp.IntActNotes
CDC27P302603EBI-10200977,EBI-994813
KRT31Q153233EBI-10200977,EBI-948001
KRT40Q6A1623EBI-10200977,EBI-10171697
KRTAP5-9P263713EBI-10200977,EBI-3958099
TRIP13Q156453EBI-372265,EBI-358993

Protein-protein interaction databases

BioGridi107707. 21 interactors.
IntActiP21964. 24 interactors.
MINTiMINT-4529967.
STRINGi9606.ENSP00000354511.

Chemistry databases

BindingDBiP21964.

Structurei

Secondary structure

1271
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi55 – 66Combined sources12
Helixi72 – 85Combined sources14
Helixi93 – 107Combined sources15
Beta strandi110 – 115Combined sources6
Beta strandi118 – 120Combined sources3
Helixi121 – 127Combined sources7
Beta strandi135 – 141Combined sources7
Helixi143 – 155Combined sources13
Helixi159 – 161Combined sources3
Beta strandi162 – 167Combined sources6
Helixi169 – 172Combined sources4
Helixi173 – 175Combined sources3
Helixi176 – 180Combined sources5
Beta strandi185 – 190Combined sources6
Helixi194 – 196Combined sources3
Helixi197 – 206Combined sources10
Beta strandi210 – 219Combined sources10
Helixi221 – 225Combined sources5
Helixi227 – 235Combined sources9
Beta strandi239 – 247Combined sources9
Beta strandi251 – 262Combined sources12

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3A7EX-ray2.80A51-264[»]
3BWMX-ray1.98A52-265[»]
3BWYX-ray1.30A52-265[»]
4PYIX-ray1.35A51-271[»]
4PYJX-ray1.90A51-271[»]
4PYKX-ray2.22A51-271[»]
4XUCX-ray1.80A48-265[»]
4XUDX-ray2.40A48-265[»]
4XUEX-ray2.30A/B52-265[»]
5LSAX-ray1.50A51-271[»]
ProteinModelPortaliP21964.
SMRiP21964.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP21964.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni167 – 170S-adenosyl-L-methionine binding4

Sequence similaritiesi

Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-dependent O-methyltransferase family.PROSITE-ProRule annotation

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1663. Eukaryota.
COG4122. LUCA.
GeneTreeiENSGT00390000011316.
HOGENOMiHOG000046392.
HOVERGENiHBG005376.
InParanoidiP21964.
KOiK00545.
OMAiGDEKGCI.
OrthoDBiEOG091G0GQK.
PhylomeDBiP21964.
TreeFamiTF329140.

Family and domain databases

Gene3Di3.40.50.150. 1 hit.
InterProiIPR017128. Catechol_O-MeTrfase_euk.
IPR002935. O-MeTrfase_3.
IPR029063. SAM-dependent_MTases.
[Graphical view]
PfamiPF01596. Methyltransf_3. 1 hit.
[Graphical view]
PIRSFiPIRSF037177. Catechol_O-mtfrase_euk. 1 hit.
SUPFAMiSSF53335. SSF53335. 1 hit.
PROSITEiPS51682. SAM_OMT_I. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

Isoform Membrane-bound (identifier: P21964-1) [UniParc]FASTAAdd to basket
Also known as: MB-COMT

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MPEAPPLLLA AVLLGLVLLV VLLLLLRHWG WGLCLIGWNE FILQPIHNLL
60 70 80 90 100
MGDTKEQRIL NHVLQHAEPG NAQSVLEAID TYCEQKEWAM NVGDKKGKIV
110 120 130 140 150
DAVIQEHQPS VLLELGAYCG YSAVRMARLL SPGARLITIE INPDCAAITQ
160 170 180 190 200
RMVDFAGVKD KVTLVVGASQ DIIPQLKKKY DVDTLDMVFL DHWKDRYLPD
210 220 230 240 250
TLLLEECGLL RKGTVLLADN VICPGAPDFL AHVRGSSCFE CTHYQSFLEY
260 270
REVVDGLEKA IYKGPGSEAG P
Length:271
Mass (Da):30,037
Last modified:May 1, 1992 - v2
Checksum:iD2547A1C399AC758
GO
Isoform Soluble (identifier: P21964-2) [UniParc]FASTAAdd to basket
Also known as: S-COMT

The sequence of this isoform differs from the canonical sequence as follows:
     1-50: Missing.

Show »
Length:221
Mass (Da):24,449
Checksum:iF17399A01E493B63
GO

Sequence cautioni

The sequence AAH00419 differs from that shown. Reason: Erroneous termination at position 85. Translated as Gln.Curated
The sequence AAH05867 differs from that shown. Reason: Erroneous termination at position 85. Translated as Gln.Curated
The sequence ACI46037 differs from that shown. Reason: Erroneous termination at position 85. Translated as Gln.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti245Q → N AA sequence (PubMed:1993083).Curated1

Mass spectrometryi

Molecular mass is 24352±2 Da from positions 52 - 271. Determined by ESI. 1 Publication

Polymorphismi

Two alleles, COMT*1 or COMT*H with Val-158 and COMT*2 or COMT*L with Met-158 are responsible for a three to four-fold difference in enzymatic activity.3 Publications
Low enzyme activity alleles are associated with genetic susceptibility to alcoholism [MIMi:103780].1 Publication

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01392534C → S.2 PublicationsCorresponds to variant rs6270dbSNPEnsembl.1
Natural variantiVAR_01392672A → S Correlated with reduced enzyme activity; could be a risk allele for schizophrenia. 3 PublicationsCorresponds to variant rs6267dbSNPEnsembl.1
Natural variantiVAR_020274102A → T.Corresponds to variant rs5031015dbSNPEnsembl.1
Natural variantiVAR_020275146A → V.Corresponds to variant rs4986871dbSNPEnsembl.1
Natural variantiVAR_005139158V → M in allele COMT*2; associated with low enzyme activity and thermolability; may increase the tendency to develop high blood pressure and abdominal obesity. 6 PublicationsCorresponds to variant rs4680dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0187781 – 50Missing in isoform Soluble. CuratedAdd BLAST50

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M65212 mRNA. Translation: AAA68927.1.
M65213 mRNA. Translation: AAA68928.1.
M58525 mRNA. Translation: AAA68929.1.
Z26491 Genomic DNA. Translation: CAA81263.1.
FJ224345 mRNA. Translation: ACI46037.1. Different termination.
AK290440 mRNA. Translation: BAF83129.1.
CR456422 mRNA. Translation: CAG30308.1.
CR456997 mRNA. Translation: CAG33278.1.
AY341246 Genomic DNA. Translation: AAP88929.1.
AC000080 Genomic DNA. No translation available.
AC000090 Genomic DNA. No translation available.
AC005663 Genomic DNA. No translation available.
CH471176 Genomic DNA. Translation: EAX03010.1.
BC000419 mRNA. Translation: AAH00419.2. Different termination.
BC005867 mRNA. Translation: AAH05867.1. Different termination.
BC011935 mRNA. Translation: AAH11935.1.
BC100018 mRNA. Translation: AAI00019.1.
CCDSiCCDS13770.1. [P21964-1]
CCDS46663.1. [P21964-2]
PIRiI37256. A38459.
RefSeqiNP_000745.1. NM_000754.3. [P21964-1]
NP_001128633.1. NM_001135161.1. [P21964-1]
NP_001128634.1. NM_001135162.1. [P21964-1]
NP_009294.1. NM_007310.2. [P21964-2]
XP_016884083.1. XM_017028594.1. [P21964-1]
XP_016884084.1. XM_017028595.1. [P21964-1]
UniGeneiHs.370408.
Hs.693979.
Hs.713616.
Hs.738526.

Genome annotation databases

EnsembliENST00000361682; ENSP00000354511; ENSG00000093010. [P21964-1]
ENST00000403710; ENSP00000385917; ENSG00000093010. [P21964-1]
ENST00000406520; ENSP00000385150; ENSG00000093010. [P21964-1]
ENST00000407537; ENSP00000384654; ENSG00000093010. [P21964-1]
ENST00000449653; ENSP00000416778; ENSG00000093010. [P21964-2]
GeneIDi1312.
KEGGihsa:1312.
UCSCiuc002zqu.4. human. [P21964-1]

Keywords - Coding sequence diversityi

Alternative initiation, Polymorphism

Cross-referencesi

Web resourcesi

NIEHS-SNPs
Wikipedia

Catechol-O-methyl transferase entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M65212 mRNA. Translation: AAA68927.1.
M65213 mRNA. Translation: AAA68928.1.
M58525 mRNA. Translation: AAA68929.1.
Z26491 Genomic DNA. Translation: CAA81263.1.
FJ224345 mRNA. Translation: ACI46037.1. Different termination.
AK290440 mRNA. Translation: BAF83129.1.
CR456422 mRNA. Translation: CAG30308.1.
CR456997 mRNA. Translation: CAG33278.1.
AY341246 Genomic DNA. Translation: AAP88929.1.
AC000080 Genomic DNA. No translation available.
AC000090 Genomic DNA. No translation available.
AC005663 Genomic DNA. No translation available.
CH471176 Genomic DNA. Translation: EAX03010.1.
BC000419 mRNA. Translation: AAH00419.2. Different termination.
BC005867 mRNA. Translation: AAH05867.1. Different termination.
BC011935 mRNA. Translation: AAH11935.1.
BC100018 mRNA. Translation: AAI00019.1.
CCDSiCCDS13770.1. [P21964-1]
CCDS46663.1. [P21964-2]
PIRiI37256. A38459.
RefSeqiNP_000745.1. NM_000754.3. [P21964-1]
NP_001128633.1. NM_001135161.1. [P21964-1]
NP_001128634.1. NM_001135162.1. [P21964-1]
NP_009294.1. NM_007310.2. [P21964-2]
XP_016884083.1. XM_017028594.1. [P21964-1]
XP_016884084.1. XM_017028595.1. [P21964-1]
UniGeneiHs.370408.
Hs.693979.
Hs.713616.
Hs.738526.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3A7EX-ray2.80A51-264[»]
3BWMX-ray1.98A52-265[»]
3BWYX-ray1.30A52-265[»]
4PYIX-ray1.35A51-271[»]
4PYJX-ray1.90A51-271[»]
4PYKX-ray2.22A51-271[»]
4XUCX-ray1.80A48-265[»]
4XUDX-ray2.40A48-265[»]
4XUEX-ray2.30A/B52-265[»]
5LSAX-ray1.50A51-271[»]
ProteinModelPortaliP21964.
SMRiP21964.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107707. 21 interactors.
IntActiP21964. 24 interactors.
MINTiMINT-4529967.
STRINGi9606.ENSP00000354511.

Chemistry databases

BindingDBiP21964.
ChEMBLiCHEMBL2023.
DrugBankiDB00286. Conjugated Estrogens.
DB00255. Diethylstilbestrol.
DB00841. Dobutamine.
DB00988. Dopamine.
DB00494. Entacapone.
DB00968. Methyldopa.
DB01141. Micafungin.
DB00118. S-Adenosylmethionine.
DB01420. Testosterone Propionate.
DB00323. Tolcapone.
GuidetoPHARMACOLOGYi2472.

PTM databases

iPTMnetiP21964.
PhosphoSitePlusiP21964.
SwissPalmiP21964.

Polymorphism and mutation databases

BioMutaiCOMT.
DMDMi116907.

2D gel databases

REPRODUCTION-2DPAGEIPI00375513.

Proteomic databases

EPDiP21964.
MaxQBiP21964.
PaxDbiP21964.
PeptideAtlasiP21964.
PRIDEiP21964.
TopDownProteomicsiP21964-1. [P21964-1]
P21964-2. [P21964-2]

Protocols and materials databases

DNASUi1312.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000361682; ENSP00000354511; ENSG00000093010. [P21964-1]
ENST00000403710; ENSP00000385917; ENSG00000093010. [P21964-1]
ENST00000406520; ENSP00000385150; ENSG00000093010. [P21964-1]
ENST00000407537; ENSP00000384654; ENSG00000093010. [P21964-1]
ENST00000449653; ENSP00000416778; ENSG00000093010. [P21964-2]
GeneIDi1312.
KEGGihsa:1312.
UCSCiuc002zqu.4. human. [P21964-1]

Organism-specific databases

CTDi1312.
DisGeNETi1312.
GeneCardsiCOMT.
HGNCiHGNC:2228. COMT.
HPAiCAB011233.
HPA001169.
MalaCardsiCOMT.
MIMi103780. phenotype.
116790. gene+phenotype.
neXtProtiNX_P21964.
OpenTargetsiENSG00000093010.
Orphaneti567. 22q11.2 deletion syndrome.
240863. Cisplatin toxicity.
3140. Schizophrenia.
PharmGKBiPA117.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1663. Eukaryota.
COG4122. LUCA.
GeneTreeiENSGT00390000011316.
HOGENOMiHOG000046392.
HOVERGENiHBG005376.
InParanoidiP21964.
KOiK00545.
OMAiGDEKGCI.
OrthoDBiEOG091G0GQK.
PhylomeDBiP21964.
TreeFamiTF329140.

Enzyme and pathway databases

BioCyciMetaCyc:HS01791-MONOMER.
ZFISH:HS01791-MONOMER.
BRENDAi2.1.1.6. 2681.
ReactomeiR-HSA-156581. Methylation.
R-HSA-379397. Enzymatic degradation of dopamine by COMT.
R-HSA-379398. Enzymatic degradation of Dopamine by monoamine oxidase.

Miscellaneous databases

ChiTaRSiCOMT. human.
EvolutionaryTraceiP21964.
GeneWikiiCatechol-O-methyl_transferase.
GenomeRNAii1312.
PROiP21964.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000093010.
CleanExiHS_COMT.
ExpressionAtlasiP21964. baseline and differential.
GenevisibleiP21964. HS.

Family and domain databases

Gene3Di3.40.50.150. 1 hit.
InterProiIPR017128. Catechol_O-MeTrfase_euk.
IPR002935. O-MeTrfase_3.
IPR029063. SAM-dependent_MTases.
[Graphical view]
PfamiPF01596. Methyltransf_3. 1 hit.
[Graphical view]
PIRSFiPIRSF037177. Catechol_O-mtfrase_euk. 1 hit.
SUPFAMiSSF53335. SSF53335. 1 hit.
PROSITEiPS51682. SAM_OMT_I. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCOMT_HUMAN
AccessioniPrimary (citable) accession number: P21964
Secondary accession number(s): A8MPV9
, Q6IB07, Q6ICE6, Q9BWC7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1991
Last sequence update: May 1, 1992
Last modified: November 30, 2016
This is version 193 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 22
    Human chromosome 22: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.