amine oxidase, copper containing 3

Target id: 2767

Nomenclature: amine oxidase, copper containing 3

Abbreviated Name: VAP-1

Family: 1.-.-.- Oxidoreductases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     amine oxidase, copper containing 3 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 763 17q21 AOC3 amine oxidase, copper containing 3 11,14
Mouse 1 765 1 B2-B5 Aoc3 amine oxidase, copper containing 3
Rat 1 736 10q32.1 Aoc3 amine oxidase, copper containing 3
Previous and Unofficial Names
HPAO | VAP1 | vascular adhesion protein 1 | amine oxidase
Database Links
BRENDA
CATH/Gene3D
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human vascular adhesion protein-1 in complex with pyridazinone inhibitor AGN-PC-0DAVGZ (PubChem CID 60172362).
PDB Id:  4BTW
Resolution:  2.8Å
Species:  Human
References:  2
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human vascular adhesion protein-1
PDB Id:  1US1
Resolution:  2.9Å
Species:  Human
References:  1
Enzyme Reaction
EC Number: 1.4.3.21

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
PXS-4728A Hs Inhibition 8.3 pIC50 10
pIC50 8.3 (IC50 5x10-9 M) [10]
phenelzine Hs Inhibition 7.7 pIC50 3
pIC50 7.7 (IC50 1.995x10-8 M) [3]
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Affinity Units Reference
timolumab Hs Binding 9.4 – 9.9 pKd 12
pKd 9.4 – 9.9 (Kd 3.8x10-10 – 1.3x10-10 M) [12]
Description: Value varies slightly between a time-resolved immunofluorometric assay and real time direct binding assay using a BIACORE® surface plasmon resonance assay.
Immunopharmacology Comments
As a membrane-bound glycoprotein. AOC3 is expressed on the surface of endothelial cells when exposed to inflammatory conditions. It has been noted to mediate binding of lymphocytes to peripheral lymph node vascular endothelial cells a process required for the recirculation of lymphocytes between blood and tissue. This activity profile has suggested AOC3 as a potential drug target for inflammatory and vascular diseases [7].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  inflammatory response (GO:0006954) TAS
References: 
Physiological Functions
Mediates binding of lymphocytes to vascular endothelial cells controlling leukocyte traffic between blood and tissues.
Species:  Human
Tissue:  Patient derived inflamed synovial membranes.
References:  6,9
General Comments
AOC3 (VAP-1) is a semicarbazide-sensitive amine oxidase, with substrate specificity which overlaps that of the monoamine oxidases (MAOs). AOC3 catalyzes the oxidative conversion of amines to aldehydes with copper and topaquinone (PubChem CID 12387) acting as cofactors. The enzyme is a membrane-bound glycoprotein. AOC3 is expressed on the surface of endothelial cells when exposed to inflammatory conditions [8] and has been noted to mediate binding of lymphocytes to peripheral lymph node vascular endothelial cells [5-6,9], a process required for the recirculation of lymphocytes between blood and tissue. This activity profile has suggested AOC3 as a potential drug target for inflammatory and vascular diseases. Specific and reversible inhibitors of AOC3 activity are in development [2,4,13], including the small molecule phenelzine and the mAb timolumab.

References

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1. Airenne TT, Nymalm Y, Kidron H, Smith DJ, Pihlavisto M, Salmi M, Jalkanen S, Johnson MS, Salminen TA. (2005) Crystal structure of the human vascular adhesion protein-1: unique structural features with functional implications. Protein Sci.14 (8): 1964-74. [PMID:16046623]

2. Bligt-Lindén E, Pihlavisto M, Szatmári I, Otwinowski Z, Smith DJ, Lázár L, Fülöp F, Salminen TA. (2013) Novel pyridazinone inhibitors for vascular adhesion protein-1 (VAP-1): old target-new inhibition mode. J. Med. Chem.56 (24): 9837-48. [PMID:24304424]

3. Nurminen EM, Pihlavisto M, Lázár L, Szakonyi Z, Pentikäinen U, Fülöp F, Pentikäinen OT. (2010) Synthesis, in vitro activity, and three-dimensional quantitative structure-activity relationship of novel hydrazine inhibitors of human vascular adhesion protein-1. J. Med. Chem.53 (17): 6301-15. [PMID:20690686]

4. O'Rourke AM, Wang EY, Miller A, Podar EM, Scheyhing K, Huang L, Kessler C, Gao H, Ton-Nu HT, Macdonald MT et al.. (2008) Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine oxidase activity. J. Pharmacol. Exp. Ther.324 (2): 867-75. [PMID:17993604]

5. Salmi M, Jalkanen S. (1992) A 90-kilodalton endothelial cell molecule mediating lymphocyte binding in humans. Science257 (5075): 1407-9. [PMID:1529341]

6. Salmi M, Jalkanen S. (1996) Human vascular adhesion protein 1 (VAP-1) is a unique sialoglycoprotein that mediates carbohydrate-dependent binding of lymphocytes to endothelial cells. J. Exp. Med.183 (2): 569-79. [PMID:8627168]

7. Salmi M, Jalkanen S. (2001) VAP-1: an adhesin and an enzyme. Trends Immunol.22 (4): 211-6. [PMID:11274927]

8. Salmi M, Kalimo K, Jalkanen S. (1993) Induction and function of vascular adhesion protein-1 at sites of inflammation. J. Exp. Med.178 (6): 2255-60. [PMID:8245796]

9. Salmi M, Rajala P, Jalkanen S. (1997) Homing of mucosal leukocytes to joints. Distinct endothelial ligands in synovium mediate leukocyte-subtype specific adhesion. J. Clin. Invest.99 (9): 2165-72. [PMID:9151788]

10. Schilter HC, Collison A, Russo RC, Foot JS, Yow TT, Vieira AT, Tavares LD, Mattes J, Teixeira MM, Jarolimek W. (2015) Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration. Respir. Res.16: 42. [PMID:25889951]

11. Smith DJ, Salmi M, Bono P, Hellman J, Leu T, Jalkanen S. (1998) Cloning of vascular adhesion protein 1 reveals a novel multifunctional adhesion molecule. J. Exp. Med.188 (1): 17-27. [PMID:9653080]

12. Smith DJ, Vainio P, Mikkola J, Vuorio P, Vainio J. (2011) Fully human anti-VAP-1 monoclonal antibodies. Patent number: US7897149 B2. Assignee: Biotie Therapies Corp.. Priority date: 20/04/2007. Publication date: 01/03/2011.

13. Wang EY, Gao H, Salter-Cid L, Zhang J, Huang L, Podar EM, Miller A, Zhao J, O'rourke A, Linnik MD. (2006) Design, synthesis, and biological evaluation of semicarbazide-sensitive amine oxidase (SSAO) inhibitors with anti-inflammatory activity. J. Med. Chem.49 (7): 2166-73. [PMID:16570912]

14. Zhang X, McIntire WS. (1996) Cloning and sequencing of a copper-containing, topa quinone-containing monoamine oxidase from human placenta. Gene179 (2): 279-86. [PMID:8972912]

How to cite this page

1.-.-.- Oxidoreductases: amine oxidase, copper containing 3. Last modified on 24/01/2017. Accessed on 24/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2767.