Copper Amine Oxidase

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<StructureSection load='2d1w' size='350' side='right' caption='Copper amine oxidase dimer showing Cu+2 (orange) complex with tyramine (PDB code [[2d1w]]).' scene=''>
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{{STRUCTURE_2d1w | PDB=2d1w | SCENE= }}
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{{STRUCTURE_2d1w| PDB=2d1w | SIZE=400| SCENE= |right|CAPTION=Copper amine oxidase showing Cu complex with tyramine, [[2d1w]] }}
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== Structure ==
== Structure ==
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[[Image:TTS.png|thumb|left|alt=3-((3E)-4-HYDROXY-3-{[2-(4-HYDROXYPHENYL)ETHYL]IMINO}-6-OXOCYCLOHEXA-1,4-DIEN-1-YL)ALANINE.|Residue 382 is a tyrosine residue, modified into topa-quinone, shown here bound to tyramine.]] 2d1w is the tyramine-bound substrate Schiff-base intermediate of [http://en.wikipedia.org/wiki/Amine_oxidase_%28copper-containing%29 copper amine oxidase] derived from [http://en.wikipedia.org/wiki/Arthrobacter_globiformis Arthrobacter globiformis]. Copper amine oxidases are classified as EC 1.4.3.6 in the EC number classification system of enzymes, and they belong to the larger class of [http://en.wikipedia.org/wiki/Oxidoreductase oxidoreductases]. The structure of this enzyme was determined by Murakawa ''et al.'' in 2005, by x-ray diffraction<ref name="Murakawa">PMID:16487484</ref>. It consists of a disulfide-linked homodimer, with each subunit containing 638 residues. Each subunit also contains a <scene name='Sandbox_Reserved_331/Copper_ligand/5'>copper ligand</scene> near the active site, which is coordinated by three histidine residues. Located near the Cu<sup>2+</sup> ligand is a tyrosine residue that has been modified into topa-quinone, which is also a cofactor in all other copper amine oxidases<ref name="Parsons">PMID:8591028</ref>. The active site of the enzyme is located near the center of the homodimer, which is connected to the outside of the enzyme by an extensively hydrated channel. It is suspected that the water helps to carry O<sub>2</sub> to the active site, as well as being used in the reaction itself<ref name="Mure">PMID:12135347</ref>.
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[[Image:TTS.png|thumb|left|alt=3-((3E)-4-HYDROXY-3-{[2-(4-HYDROXYPHENYL)ETHYL]IMINO}-6-OXOCYCLOHEXA-1,4-DIEN-1-YL)ALANINE.|Residue 382 is a tyrosine residue, modified into topa-quinone, shown here bound to tyramine.]]
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'''Copper amine oxidases''' or '''primary amine oxidase''' (CuAO) are classified as EC 1.4.3.6 in the EC number classification system of enzymes, and they belong to the larger class of [http://en.wikipedia.org/wiki/Oxidoreductase oxidoreductases]. [[2d1w]] is the tyramine-bound substrate Schiff-base intermediate of [http://en.wikipedia.org/wiki/Amine_oxidase_%28copper-containing%29 copper amine oxidase] derived from [http://en.wikipedia.org/wiki/Arthrobacter_globiformis Arthrobacter globiformis]. The structure of this enzyme was determined by Murakawa ''et al.'' in 2005, by x-ray diffraction<ref name="Murakawa">PMID:16487484</ref>. It consists of a disulfide-linked homodimer, with each subunit containing 638 residues. Each subunit also contains a <scene name='Sandbox_Reserved_331/Copper_ligand/5'>copper ligand</scene> near the active site, which is coordinated by three histidine residues. Located near the Cu<sup>2+</sup> ligand is a tyrosine residue that has been modified into topa-quinone ('''TPQ'''), which is also a cofactor in all other copper amine oxidases<ref name="Parsons">PMID:8591028</ref>. The active site of the enzyme is located near the center of the homodimer, which is connected to the outside of the enzyme by an extensively hydrated channel. It is suspected that the water helps to carry O<sub>2</sub> to the active site, as well as being used in the reaction itself<ref name="Mure">PMID:12135347</ref>. <scene name='43/433611/Cv/1'>Cu coordination site</scene>. Water molecules are shown as red spheres.
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CuAO from ''Arthrobacter globiformis'' is called '''phenylethylamine oxidase''' undergoes reduction of phenylethylamine and forms phenylacetaldehyde.
== Reaction Mechanism ==
== Reaction Mechanism ==
Copper amine oxidase catalyzes the oxidation of a primary amine to the corresponding aldehyde, yielding hydrogen peroxide and free ammonia. An example of this is the oxidation of [http://en.wikipedia.org/wiki/Tyramine tyramine]:
Copper amine oxidase catalyzes the oxidation of a primary amine to the corresponding aldehyde, yielding hydrogen peroxide and free ammonia. An example of this is the oxidation of [http://en.wikipedia.org/wiki/Tyramine tyramine]:
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[[Image:Tyramine oxidation.png|thumb|center|600px|The oxidation of tyramine, yielding the corresponding aldehyde, hydrogen peroxide, and ammonia.]]
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[[Image:Tyramine oxidation.png|thumb|center|400px|The oxidation of tyramine, yielding the corresponding aldehyde, hydrogen peroxide, and ammonia.]]
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=== Reductive half-reaction ===
=== Reductive half-reaction ===
In the reductive half-reaction, the carbonyl of topa-quinone reacts with the primary amine of the substrate, forming the substrate Schiff-base intermediate ([http://www.proteopedia.org/wiki/index.php/2cwv 2cwv]). The α-proton is then abstracted by a conserved aspartic acid residue (Asp298), which forms the product Schiff-base intermediate ([http://www.proteopedia.org/wiki/index.php/2cwv 2cwv]). Several studies have shown that the abstraction of the α-proton proceeds through [http://en.wikipedia.org/wiki/Quantum_tunnelling quantum-mechanical tunneling], which allows the proton to pass through an energy barrier which it would otherwise not be able to pass according to classical mechanics<ref name="Murakawa" /><ref name="Grant">PMID:2790014</ref>.This bond is then hydrolyzed, which yields the aldehyde form of the substrate, the aminoquinol form of topa-quinone, and a proton.
In the reductive half-reaction, the carbonyl of topa-quinone reacts with the primary amine of the substrate, forming the substrate Schiff-base intermediate ([http://www.proteopedia.org/wiki/index.php/2cwv 2cwv]). The α-proton is then abstracted by a conserved aspartic acid residue (Asp298), which forms the product Schiff-base intermediate ([http://www.proteopedia.org/wiki/index.php/2cwv 2cwv]). Several studies have shown that the abstraction of the α-proton proceeds through [http://en.wikipedia.org/wiki/Quantum_tunnelling quantum-mechanical tunneling], which allows the proton to pass through an energy barrier which it would otherwise not be able to pass according to classical mechanics<ref name="Murakawa" /><ref name="Grant">PMID:2790014</ref>.This bond is then hydrolyzed, which yields the aldehyde form of the substrate, the aminoquinol form of topa-quinone, and a proton.
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[[Image:2d1wReductive Half.png|thumb|center|800px|The reductive half-reaction in the oxidation of a primary amine by copper amine oxidase.]]
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[[Image:2d1wReductive Half.png|thumb|center|400px|The reductive half-reaction in the oxidation of a primary amine by copper amine oxidase.]]
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=== Oxidative half-reaction ===
=== Oxidative half-reaction ===
In the oxidative half-reaction, electrons are transferred from the reduced form of topa-quinone to O<sub>2</sub>, forming a superoxide ion that is stabilized by the Cu<sup>2+</sup> ligand. Reduction of the superoxide by the amino-quinone form of topa-quinone yields peroxide and the imino-quinone form, leading to the release of hydrogen peroxide. Hydrolysis of the imino-quinone form of topa-quinone then releases free ammonia, and regenerates the oxidized form of topa-quinone<ref name="Grant" />.
In the oxidative half-reaction, electrons are transferred from the reduced form of topa-quinone to O<sub>2</sub>, forming a superoxide ion that is stabilized by the Cu<sup>2+</sup> ligand. Reduction of the superoxide by the amino-quinone form of topa-quinone yields peroxide and the imino-quinone form, leading to the release of hydrogen peroxide. Hydrolysis of the imino-quinone form of topa-quinone then releases free ammonia, and regenerates the oxidized form of topa-quinone<ref name="Grant" />.
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[[Image:2d1w Oxidative Half.png|thumb|center|800px|The oxidative half-reaction, in which topa-quinone is restored to its oxidized form, releasing ammonia and hydrogen peroxide.]]
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[[Image:2d1w Oxidative Half.png|thumb|center|400px|The oxidative half-reaction, in which topa-quinone is restored to its oxidized form, releasing ammonia and hydrogen peroxide.]]
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==3D structures of copper amine oxidase ==
==3D structures of copper amine oxidase ==
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[[Copper amine oxidase 3D structures]]
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''Update November 2011''
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</StructureSection>
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[[1us1]], [[1pu4]], [[2y73]] , [[2y74]] – hCuAO – human<br />
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[[3ala]], [[2c10]] – hCuAO residues 33-763<br />
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[[3loy]], [[2oov]], [[2oqe]] - PaCuAO – ''Pichia angusta''<br />
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[[3n9h]], [[3nbb]], [[3nbj]] – PaCuAO (mutant) <br />
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[[2wo0]], [[2wof]], [[2woh]], [[2w0q]], [[1d6u]], [[1spu]], [[1oac]] – EcCuAO residues 31-757 – E''scherichia coli''<br />
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[[1jrq]], [[1qak]], [[1qal]], [[1qaf]] - EcCuAO (mutant) <br />
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[[1w6c]], [[1w6g]], [[1rjo]] – AgCuAO – ''Arthrobacter globiformis''<br />
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[[1ui7]], [[1ui8]], [[2d1w]] - AgCuAO (mutant) <br />
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[[1tu5]] – bCuAO – bovine<br />
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[[1ksi]] – CuAO – pea
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===Copper amine oxidase binary complex===
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[[2pnc]] – bCuAO + clonidine<br />
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[[2c11]] - hCuAO + hydrazine derivative<br />
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[[2e2t]], [[2e2u]], [[2e2v]], [[1w5z]] – AgCuAO + hydrazine derivative <br />
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[[2cfd]], [[2cfg]], [[2cfk]], [[2cfl]], [[2cfw]], [[2cg0]], [[2cg1]], [[1w4n]], [[2bt3]] – AgCuAO + inhibitor<br />
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[[1lvn]] - EcCuAO + inhibitor<br />
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[[1dyu]] – EcCuAO + quinone cofactor<br />
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[[1d6y]] – EcCuAO + NO2<br />
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[[1d6z]] – EcCuAO + catalytic intermediate
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===Zinc-substituted copper amine oxidase===
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[[2wgq]] – EcZnAO<br />
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[[1ekm]] - PaZnAO
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= Additional Resources =
= Additional Resources =

Current revision

Copper amine oxidase dimer showing Cu+2 (orange) complex with tyramine (PDB code 2d1w).

Drag the structure with the mouse to rotate

Additional Resources


References

  1. ↑ 1.0 1.1 Murakawa T, Okajima T, Kuroda S, Nakamoto T, Taki M, Yamamoto Y, Hayashi H, Tanizawa K. Quantum mechanical hydrogen tunneling in bacterial copper amine oxidase reaction. Biochem Biophys Res Commun. 2006 Apr 7;342(2):414-23. Epub 2006 Feb 8. PMID:16487484 doi:10.1016/j.bbrc.2006.01.150
  2. ↑ Parsons MR, Convery MA, Wilmot CM, Yadav KD, Blakeley V, Corner AS, Phillips SE, McPherson MJ, Knowles PF. Crystal structure of a quinoenzyme: copper amine oxidase of Escherichia coli at 2 A resolution. Structure. 1995 Nov 15;3(11):1171-84. PMID:8591028
  3. ↑ Mure M, Mills SA, Klinman JP. Catalytic mechanism of the topa quinone containing copper amine oxidases. Biochemistry. 2002 Jul 30;41(30):9269-78. PMID:12135347
  4. ↑ 4.0 4.1 Grant KL, Klinman JP. Evidence that both protium and deuterium undergo significant tunneling in the reaction catalyzed by bovine serum amine oxidase. Biochemistry. 1989 Aug 8;28(16):6597-605. PMID:2790014

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