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amine oxidase copper containing 3

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2767

Nomenclature: amine oxidase copper containing 3

Abbreviated Name: VAP-1

Family: 1.-.-.- Oxidoreductases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 763 17q21.31 AOC3 amine oxidase copper containing 3 14,17
Mouse 1 765 11 D Aoc3 amine oxidase, copper containing 3
Rat 1 763 10q31 Aoc3 amine oxidase, copper containing 3
Previous and Unofficial Names Click here for help
amine oxidase | amine oxidase, copper containing 3 | HPAO | semicarbazide-sensitive amine oxidase | SSAO | VAP1 | vascular adhesion protein 1
Database Links Click here for help
Alphafold Q16853 (Hs), O70423 (Mm), O08590 (Rn)
BRENDA 1.4.3.21
CATH/Gene3D 2.70.98.20
ChEMBL Target CHEMBL3437 (Hs), CHEMBL4727 (Mm), CHEMBL4592 (Rn)
DrugBank Target Q16853 (Hs)
Ensembl Gene ENSG00000131471 (Hs), ENSMUSG00000019326 (Mm), ENSRNOG00000051307 (Rn)
Entrez Gene 8639 (Hs), 11754 (Mm), 29473 (Rn)
Human Protein Atlas ENSG00000131471 (Hs)
KEGG Enzyme 1.4.3.21
KEGG Gene hsa:8639 (Hs), mmu:11754 (Mm), rno:29473 (Rn)
OMIM 03735 (Hs)
Pharos Q16853 (Hs)
RefSeq Nucleotide NM_003734 (Hs), NM_009675 (Mm), NM_031582 (Rn)
RefSeq Protein NP_003725 (Hs), NP_033805 (Mm), NP_113770 (Rn)
UniProtKB Q16853 (Hs), O70423 (Mm), O08590 (Rn)
Wikipedia AOC3 (Hs)
Selected 3D Structures Click here for help
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 Click here for help
EC Number: 1.4.3.21

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PXS-4681A Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Irreversible inhibition 7.4 pKi 4
⤷ pKi 7.4 (Ki 3.7x10-8 M) [4]
PXS-4681A Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Irreversible inhibition 8.5 pIC50 4
⤷ pIC50 8.5 (IC50 3x10-9 M) [4]
Description: Inhibition of recombinant hSSAO.
PXS-4728A Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 13
⤷ pIC50 8.3 (IC50 5x10-9 M) [13]
mofegiline Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 7.7 pIC50 4
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [4]
Description: Inhibition of recombinant hSSAO/VAP-1.
phenelzine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 7.7 pIC50 6
⤷ pIC50 7.7 (IC50 1.995x10-8 M) [6]
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
timolumab Peptide Primary target of this compound Immunopharmacology Ligand Hs Binding 9.4 – 9.9 pKd 15
⤷ pKd 9.4 – 9.9 (Kd 3.8x10-10 – 1.3x10-10 M) [15]
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 (a.k.a. SSAO, VAP-1) 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 [10]. The clinical potential of AOC3 inhibitors is reviewed in a patent survey [3] and an Annual Reports in Medicinal Chemistry article [5].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Immune regulation
Physiological Functions Click here for help
Mediates binding of lymphocytes to vascular endothelial cells controlling leukocyte traffic between blood and tissues.
Species:  Human
Tissue:  Patient derived inflamed synovial membranes.
References:  9,12
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 [11] and has been noted to mediate binding of lymphocytes to peripheral lymph node vascular endothelial cells [8-9,12], 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 [2,7,16], 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. Dunkel P, Balogh B, Meleddu R, Maccioni E, Gyires K, Mátyus P. (2011) Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1: a patent survey. Expert Opin Ther Pat, 21 (9): 1453-71. [PMID:21675926]

4. Foot JS, Yow TT, Schilter H, Buson A, Deodhar M, Findlay AD, Guo L, McDonald IA, Turner CI, Zhou W et al.. (2013) PXS-4681A, a potent and selective mechanism-based inhibitor of SSAO/VAP-1 with anti-inflammatory effects in vivo. J Pharmacol Exp Ther, 347 (2): 365-74. [PMID:23943052]

5. McDonald IA, Foot JS, Yin P, Fleming E, van Dam EM. (2007) Semicarbazide-sensitive amine oxidase and vascular adhesion protein-1: One protein being validated as a therapeutic target for inflammatory diseases. Annu Rep Med Chem, 42: 229–243.

6. 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]

7. 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]

8. Salmi M, Jalkanen S. (1992) A 90-kilodalton endothelial cell molecule mediating lymphocyte binding in humans. Science, 257 (5075): 1407-9. [PMID:1529341]

9. 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]

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

11. 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]

12. 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]

13. 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]

14. 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]

15. 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.

16. 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]

17. Zhang X, McIntire WS. (1996) Cloning and sequencing of a copper-containing, topa quinone-containing monoamine oxidase from human placenta. Gene, 179 (2): 279-86. [PMID:8972912]

How to cite this page

1.-.-.- Oxidoreductases: amine oxidase copper containing 3. Last modified on 27/03/2019. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2767.