Primary-amine oxidase
A group of enzymes that oxidise primary monoamines but have little or no activity towards diamines, such as histamine, or towards secondary and tertiary amines. They are copper quinoproteins (2,4,5-trihydroxyphenylalanine quinone) and are sensitive to inhibition by carbonyl-group reagents, such as semicarbazide. In some mammalian tissues the enzyme also functions as a vascular-adhesion protein (VAP-1).
Reference Protein and Structure
- Sequence
-
P46883
(1.4.3.21)
(Sequence Homologues)
(PDB Homologues)
- Biological species
-
Escherichia coli K-12 (Bacteria)
- PDB
-
1oac
- CRYSTAL STRUCTURE OF A QUINOENZYME: COPPER AMINE OXIDASE OF ESCHERICHIA COLI AT 2 ANGSTROEMS RESOLUTION
(2.0 Å)
- Catalytic CATH Domains
-
2.70.98.20
(see all for 1oac)
- Cofactors
- Copper(2+) (1)
Enzyme Reaction (EC:1.4.3.21)
+
+
→
+
+
Alternative enzyme names: Amine oxidase, Amine oxidase (copper-containing), Amine oxidase (pyridoxal containing), Benzylamine oxidase, CAO, Copper amine oxidase, Cu-amine oxidase, Cu-containing amine oxidase, Diamine oxidase, Diamino oxhydrase, Histamine deaminase, Histamine oxidase, Monoamine oxidase, Plasma monoamine oxidase, Polyamine oxidase, Semicarbazide-sensitive amine oxidase, SSAO,
Enzyme Mechanism
Introduction
The substrate is first deprotonated and then forms the substrate Schiff base C5 (step 1). Asp383 then abstracts a hydrogen from the methylene group (step 2), and a rearrangement leads to the product Schiff base (step 3). Hydrolysis releases the product aldehyde, leaving the enzyme in a reduced state (step 4). Reoxidation of the enzyme by molecular oxygen releases ammonia and hydrogen peroxide, and regenerates the active form
Catalytic Residues Roles
| UniProt | PDB* (1oac) | ||
| Tyr496 (ptm) | Tpq466A (ptm) | Tyr466 is post-translationally modified to a topaquinone cofactor (CHEBI:79027). During the course of the reaction, this residue becomes covalently attached to the substrate amine via a Schiff-base. This residue also forms part of the copper binding site. | covalent catalysis |
| His554, His556, His719 | His524A, His526A, His689A | Forms part of the copper binding site. | metal ligand |
| Tyr399 | Tyr369A | The Tyr369 residue appears to play an important role in stabilising the position of the quinone/inhibitor complex. Although there has been some debate as to exactly how critical this conserved residue is. | electrostatic stabiliser |
| Asp413 | Asp383A | Asp-383 facilitates TCP binding by accepting a proton from the protonated amine in step (i) and donating a proton back to the unstable charge-distributed oxyanion species in step (iii), thus enhancing the rate of formation of the substrate Schiff base. It also acts to regulate the mobility of the topaquinone cofactor that is essential to catalysis. | proton shuttle (general acid/base) |
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file;
y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain;
C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.
Chemical Components
References
- Murray JM et al. (1999), Biochemistry, 38, 8217-8227. The active site base controls cofactor reactivity in Escherichia coli amine oxidase: x-ray crystallographic studies with mutational variants. DOI:10.1021/bi9900469. PMID:10387067.
- Chen ZW et al. (2010), Biochemistry, 49, 7393-7402. Mutation at a strictly conserved, active site tyrosine in the copper amine oxidase leads to uncontrolled oxygenase activity. DOI:10.1021/bi100643y. PMID:20684524.
- Smith MA et al. (2010), Biochemistry, 49, 1268-1280. Exploring the roles of the metal ions in Escherichia coli copper amine oxidase. DOI:10.1021/bi901738k. PMID:20052994.
- Moore RH et al. (2007), J Am Chem Soc, 129, 11524-11534. Trapping of a dopaquinone intermediate in the TPQ cofactor biogenesis in a copper-containing amine oxidase from Arthrobacter globiformis. DOI:10.1021/ja0731165. PMID:17715921.
- Chiu YC et al. (2006), Biochemistry, 45, 4105-4120. Kinetic and structural studies on the catalytic role of the aspartic acid residue conserved in copper amine oxidase. DOI:10.1021/bi052464l. PMID:16566584.
- Mure M et al. (2005), Biochemistry, 44, 1583-1594. Active site rearrangement of the 2-hydrazinopyridine adduct in Escherichia coli amine oxidase to an azo copper(II) chelate form: a key role for tyrosine 369 in controlling the mobility of the TPQ-2HP adduct. DOI:10.1021/bi0479860. PMID:15683242.
- Mure M et al. (2005), Biochemistry, 44, 1568-1582. Role of the interactions between the active site base and the substrate Schiff base in amine oxidase catalysis. Evidence from structural and spectroscopic studies of the 2-hydrazinopyridine adduct of Escherichia coli amine oxidase. DOI:10.1021/bi047988k. PMID:15683241.
- Prabhakar R et al. (2004), J Am Chem Soc, 126, 3996-4006. A theoretical study of the mechanism for the biogenesis of cofactor topaquinone in copper amine oxidases. DOI:10.1021/ja034721k. PMID:15038754.
- Saysell CG et al. (2002), Biochem J, 365, 809-816. Probing the catalytic mechanism of Escherichia coli amine oxidase using mutational variants and a reversible inhibitor as a substrate analogue. DOI:10.1042/BJ20011435. PMID:11985492.
- Murray JM et al. (2001), Biochemistry, 40, 12808-12818. Conserved Tyrosine-369 in the Active Site ofEscherichia coliCopper Amine Oxidase Is Not Essential†,‡. DOI:10.1021/bi011187p.
- Wilmot CM et al. (1999), Science, 286, 1724-1728. Visualization of dioxygen bound to copper during enzyme catalysis. PMID:10576737.
- Wilmot CM et al. (1997), Biochemistry, 36, 1608-1620. Catalytic mechanism of the quinoenzyme amine oxidase from Escherichia coli: exploring the reductive half-reaction. DOI:10.1021/bi962205j. PMID:9048544.
Catalytic Residues Roles
| Residue | Roles |
|---|---|
| Tpq466A (ptm) | covalent catalysis |
| Asp383A | proton shuttle (general acid/base) |
| His524A | metal ligand |
| His526A | metal ligand |
| His689A | metal ligand |
| Tyr369A | electrostatic stabiliser |