DB code: S00291

RLCP classification 3.707.90500.391 : Transfer
CATH domain 3.40.50.150 : Rossmann fold Catalytic domain
E.C. 2.1.1.6
CSA 1vid
M-CSA 1vid
MACiE

CATH domain Related DB codes (homologues)
3.40.50.150 : Rossmann fold S00637 S00639 S00262 S00261 S00412 D00075 D00076 D00079 D00080 D00082 D00083 D00823

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P22734 Catechol O-methyltransferase
EC 2.1.1.6
NP_036663.1 (Protein)
NM_012531.2 (DNA/RNA sequence)
PF01596 (Methyltransf_3)
[Graphical View]
P21964 Catechol O-methyltransferase
EC 2.1.1.6
NP_000745.1 (Protein)
NM_000754.3 (DNA/RNA sequence)
NP_001128633.1 (Protein)
NM_001135161.1 (DNA/RNA sequence)
NP_001128634.1 (Protein)
NM_001135162.1 (DNA/RNA sequence)
NP_009294.1 (Protein)
NM_007310.2 (DNA/RNA sequence)
PF01596 (Methyltransf_3)
[Graphical View]

KEGG enzyme name
catechol O-methyltransferase
COMT I
COMT II
S-COMT (soluble form of catechol-O-methyltransferase)
MB-COMT (membrane-bound form of catechol-O-methyltransferase)
catechol methyltransferase
catecholamine O-methyltransferase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P22734 COMT_RAT S-adenosyl-L-methionine + a catechol = S-adenosyl-L-homocysteine + a guaiacol. Isoform 2: Cytoplasm. Isoform 1: Cell membrane, Single-pass type II membrane protein, Extracellular side. Binds 1 magnesium ion per subunit.
P21964 COMT_HUMAN S-adenosyl-L-methionine + a catechol = S-adenosyl-L-homocysteine + a guaiacol. Isoform Soluble: Cytoplasm. Isoform Membrane-bound: Cell membrane, Single-pass type II membrane protein, Extracellular side. Binds 1 magnesium ion per subunit.

KEGG Pathways
Map code Pathways E.C.
MAP00350 Tyrosine metabolism

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00019 C00090 C02012 C00788 C00547 C00021 C01502
E.C.
Compound Magnesium S-Adenosyl-L-methionine Catechol Catecholamine (R)-(-)-Adrenaline Noradrenaline S-Adenosyl-L-homocysteine Guaiacol
Type divalent metal (Ca2+, Mg2+) amino acids,amine group,nucleoside,sulfonium ion aromatic ring (only carbon atom) amine group,aromatic ring (only carbon atom) amine group,aromatic ring (only carbon atom),carbohydrate amine group,aromatic ring (only carbon atom),carbohydrate amino acids,amine group,nucleoside,sulfide group aromatic ring (only carbon atom),carbohydrate
ChEBI 18420
 18420
 		67040
 67040
 		18135
 18135
 		28918
 28918
 		18357
 18357
 		16680
 57856
 16680
 57856
 		28591
 28591
PubChem 888
 888
 		34755
 34755
 		289
 289
 		5816
 5816
 		439260
 439260
 		25246222
 439155
 25246222
 439155
 		460
 460
1vidA Bound:_MG Bound:SAM Analogue:DNC Unbound Unbound Unbound Unbound Unbound
1h1dA Bound:_MG Bound:SAM Unbound Analogue:BIA Unbound Unbound Unbound Unbound
1jr4A Bound:_MG Analogue:CL4 Analogue:CL4 Unbound Unbound Unbound Unbound Unbound
2cl5A Bound:_MG Bound:SAM Analogue:BIE Unbound Unbound Unbound Unbound Unbound
2cl5B Bound:_MG Bound:SAM Analogue:BIE Unbound Unbound Unbound Unbound Unbound
2zlbA Unbound Unbound Unbound Unbound Unbound Unbound Unbound Unbound
2zthA Bound:_MG Bound:SAM Unbound Unbound Unbound Unbound Unbound Unbound
2zvjA Bound:_MG Bound:SAM Analogue:KOM Unbound Unbound Unbound Unbound Unbound
3a7dA Bound:_MG Analogue:FBN Analogue:FBN Unbound Unbound Unbound Unbound Unbound
3hvhA Bound:_MG Analogue:542 Analogue:542 Unbound Unbound Unbound Unbound Unbound
3hviA Bound:_MG Analogue:619 Analogue:619 Unbound Unbound Unbound Unbound Unbound
3hvjA Bound:_MG Analogue:705 Analogue:705 Unbound Unbound Unbound Unbound Unbound
3hvjB Bound:_MG Analogue:705 Analogue:705 Unbound Unbound Unbound Unbound Unbound
3hvkA Bound:_MG Analogue:719 Analogue:719 Unbound Unbound Unbound Unbound Unbound
3a7eA Bound:_MG Bound:SAM Analogue:DNC Unbound Unbound Unbound Unbound Unbound
3bwmA Bound:_MG Bound:SAM Analogue:DNC Unbound Unbound Unbound Unbound Unbound
3bwyA Bound:_MG Bound:SAM Analogue:DNC Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1vidA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
1h1dA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
1jr4A LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
2cl5A LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
2cl5B LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
2zlbA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
2zthA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
2zvjA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
3a7dA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
3hvhA LYS 187;GLU 242 ASP 184;ASP 212;ASN 213(Magnesium binding)
3hviA LYS 187;GLU 242 ASP 184;ASP 212;ASN 213(Magnesium binding)
3hvjA LYS 187;GLU 242 ASP 184;ASP 212;ASN 213(Magnesium binding)
3hvjB LYS 187;GLU 242 ASP 184;ASP 212;ASN 213(Magnesium binding)
3hvkA LYS 187;GLU 242 ASP 184;ASP 212;ASN 213(Magnesium binding)
3a7eA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
3bwmA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding)
3bwyA LYS 144;GLU 199 ASP 141;ASP 169;ASN 170(Magnesium binding) mutant V108M

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[2]
p.356
[4]
Fig.1
[5]
p.276-277
[7]
p.804
[10]
p.496
[11]
p.136-138

References
[1]
Resource
Comments
Medline ID
PubMed ID 1749777
Journal Proteins
Year 1991
Volume 11
Pages 233-6
Authors Vidgren J, Tilgmann C, Lundstrom K, Liljas A
Title Crystallization and preliminary X-ray investigation of a recombinant form of rat catechol O-methyltransferase.
Related PDB
Related UniProtKB
[2]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF SOLUBLE FORM.; rat
Medline ID
PubMed ID 8127373
Journal Nature
Year 1994
Volume 368
Pages 354-8
Authors Vidgren J, Svensson LA, Liljas A
Title Crystal structure of catechol O-methyltransferase.
Related PDB 1vid
Related UniProtKB P22734
[3]
Resource
Comments
Medline ID
PubMed ID 7703232
Journal Biochemistry
Year 1995
Volume 34
Pages 4202-10
Authors Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J
Title Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 10785817
Journal Chemistry
Year 2000
Volume 6
Pages 971-82
Authors Masjost B, Ballmer P, Borroni E, Zurcher G, Winkler FK, Jakob-Roetne R, Diederich F
Title Structure-based design, synthesis, and in vitro evaluation of bisubstrate inhibitors for catechol O-methyltransferase (COMT).
Related PDB
Related UniProtKB
[5]
Resource
Comments X-RAY CRYSTALLOGRAPHY; very distant homologue (plant)
Medline ID
PubMed ID 11224575
Journal Nat Struct Biol
Year 2001
Volume 8
Pages 271-9
Authors Zubieta C, He XZ, Dixon RA, Noel JP
Title Structures of two natural product methyltransferases reveal the basis for substrate specificity in plant O-methyltransferases.
Related PDB 1fpq 1fp1 1fpx 1fp2
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 12404486
Journal Angew Chem Int Ed Engl
Year 2001
Volume 40
Pages 4040-4042
Authors Lerner C, Ruf A, Gramlich V, Masjost B, Zurcher G, Jakob-Roetne R, Borroni E, Diederich F
Title X-ray Crystal Structure of a Bisubstrate Inhibitor Bound to the Enzyme Catechol-O-methyltransferase: A Dramatic Effect of Inhibitor Preorganization on Binding Affinity We thank F. Hoffmann-La Roche for generous support of this work. We are grateful to P. Malherbe for the cloning of COMT, P. Caspers for the expression of COMT, A. Cesura for enzyme purification, B. Wipf for fermentation, and H. W. Lahm for sequencing. .
Related PDB 1jr4
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 12237326
Journal Mol Pharmacol
Year 2002
Volume 62
Pages 795-805
Authors Bonifacio MJ, Archer M, Rodrigues ML, Matias PM, Learmonth DA, Carrondo MA, Soares-Da-Silva P
Title Kinetics and crystal structure of catechol-o-methyltransferase complex with co-substrate and a novel inhibitor with potential therapeutic application.
Related PDB 1h1d
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 16618795
Journal Mol Pharmacol
Year 2006
Volume 70
Pages 143-53
Authors Palma PN, Rodrigues ML, Archer M, Bonifacio MJ, Loureiro AI, Learmonth DA, Carrondo MA, Soares-da-Silva P
Title Comparative study of ortho- and meta-nitrated inhibitors of catechol-O-methyltransferase: interactions with the active site and regioselectivity of O-methylation.
Related PDB 2cl5
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 18486144
Journal J Mol Biol
Year 2008
Volume 380
Pages 120-30
Authors Rutherford K, Le Trong I, Stenkamp RE, Parson WW
Title Crystal structures of human 108V and 108M catechol O-methyltransferase.
Related PDB 3bwm 3bwy
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 19056347
Journal Biochem Biophys Res Commun
Year 2009
Volume 378
Pages 494-7
Authors Tsuji E, Okazaki K, Takeda K
Title Crystal structures of rat catechol-O-methyltransferase complexed with coumarine-based inhibitor.
Related PDB 2zvj
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 19111934
Journal J Struct Biol
Year 2009
Volume 165
Pages 133-9
Authors Tsuji E, Okazaki K, Isaji M, Takeda K
Title Crystal structures of the apo and holo form of rat catechol-O-methyltransferase.
Related PDB 2zlb 2zth
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 19882607
Journal Angew Chem Int Ed Engl
Year 2009
Volume 48
Pages 9092-6
Authors Ellermann M, Jakob-Roetne R, Lerner C, Borroni E, Schlatter D, Roth D, Ehler A, Rudolph MG, Diederich F
Title Molecular recognition at the active site of catechol-o-methyltransferase: energetically favorable replacement of a water molecule imported by a bisubstrate inhibitor.
Related PDB 3hvh 3hvi 3hvj 3hvk
Related UniProtKB

Comments
According to the literature [5], which describes the mechanisms of the homologues of this enzymes, O-methyltransferases, methylation most likely proceeds via base-assisted deprotonation of the hydroxyl group followed by a nucleophilic attack of the newly generated phenolate anion of the substrate on the ractive methyl group of SAM. Because the sulfur of SAM is positively charged, the transmethylation process is easily facilitated by the deprotonation step. In catechol O-methyltransferase, O-methylation reaction is facilitated by metal-mediated deprotonation.
The literature [2] suggests that the methyl transfer from SAM to the catechol substrate catalysed by this enzyme is a direct bimolecular transfer of the methyl group from the sulfur of SAM to the oxygen of the catchol hydroxyl in an SN2-like transition state. One of the hydroxyl group of the substrate is surrounded by three positively charged groups inducing it to release its proton to become a negatively charged phenolate ion. These moieties are the Mg2+, the methyl group of SAM, and Lys144. The Mg2+ ion in particular probably lowers the pKa of the hydroxyl group significantly. In contrast, the proton of the other hydroxyl group is stabilized by the negatively charged carboxyl group of Glu199. The ionized hydroxyl makes a direct nucleophilic attack on the electron-deficient methyl of SAM.

Created Updated
2002-05-01 2010-12-02