myeloperoxidase | 1.-.-.- Oxidoreductases | IUPHAR Guide to IMMUNOPHARMACOLOGY

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myeloperoxidase

Target id: 2789

Nomenclature: myeloperoxidase

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: ON :     myeloperoxidase has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 745 17q21.3-q23 MPO myeloperoxidase
Mouse - 718 11 C Mpo myeloperoxidase
Rat - 458 10q26 Mpo myeloperoxidase
Database Links
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

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
PF-06282999 Hs Inhibition 6.5 pKi 9
pKi 6.5 (Ki 3.16x10-7 M) [9]
Description: Inhibition of the peroxidase activity of MPO isolated from human polynuclear leukocytes.
compound 28 [PMID: 28671460] Hs Inhibition 7.4 pIC50 10
pIC50 7.4 (IC50 4.4x10-8 M) [10]
aminopyridine 2 Hs Inhibition 6.8 pIC50 6
pIC50 6.8 (IC50 1.6x10-7 M) [6]
Description: In a fluorescent MPO peroxidation biochemical assay.
AZD5904 Hs Inhibition 6.7 pIC50 11
pIC50 6.7 (IC50 2x10-7 M) [11]
Description: Inhibition of the chlorination activity of MPO
verdiperstat Hs Inhibition 6.2 pIC50 2
pIC50 6.2 (IC50 6.3x10-7 M) [2]
Description: In a biochemical in vitro assay.
Inhibitor Comments
The ex vivo IC50 for inhibition of MPO activity by aminopyridine 2 is 1900 nM in human plasma [6].
Physiological Consequences of Altering Gene Expression
Over-expression of MPO in hematopoietic cells exacerbates atherogenesis in mice.
Species:  Mouse
Tissue:  Hematopoietic cells.
Technique:  Transgenic over-expression.
References:  3,7
MPO deficient mice are protected in a model of myocardial infarction.
Species:  Mouse
Tissue: 
Technique: 
References:  1
Clinically-Relevant Mutations and Pathophysiology
Disease:  Alzheimer disease
Synonyms: Alzheimer's disease [Disease Ontology: DOID:10652]
Disease Ontology: DOID:10652
OMIM: 104300
Disease:  Myeloperoxidase deficiency; MPOD
OMIM: 254600
Orphanet: ORPHA2587
General Comments
Myeloperoxidase (MPO) is a heme enzyme that participates in the formation of microbicidal reactive oxidants. It is most abundantly expressed in neutrophil granulocytes. MPO released from neutrophils and monocytes catalyzes the formation of reactive chlorinating species that are capable of oxidizing proteins and altering biological function.

References

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1. Askari AT, Brennan ML, Zhou X, Drinko J, Morehead A, Thomas JD, Topol EJ, Hazen SL, Penn MS. (2003) Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction. J. Exp. Med., 197 (5): 615-24. [PMID:12615902]

2. AstraZeneca. AZD3241. Accessed on 20/08/2018. Modified on 20/08/2018. ncats.nih.gov, https://ncats.nih.gov/files/AZD3241-2016.pdf

3. Castellani LW, Chang JJ, Wang X, Lusis AJ, Reynolds WF. (2006) Transgenic mice express human MPO -463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in -463G males. J. Lipid Res., 47 (7): 1366-77. [PMID:16639078]

4. Klebanoff SJ. (2005) Myeloperoxidase: friend and foe. J. Leukoc. Biol., 77 (5): 598-625. [PMID:15689384]

5. Malle E, Furtmüller PG, Sattler W, Obinger C. (2007) Myeloperoxidase: a target for new drug development?. Br. J. Pharmacol., 152 (6): 838-54. [PMID:17592500]

6. Marro ML, Patterson AW, Lee L, Deng L, Reynolds A, Ren X, Axford L, Patnaik A, Hollis-Symynkywicz M, Casson N et al.. (2018) Discovery of 1-((6-Aminopyridin-3-yl)Methyl)-3-(4-Bromophenyl)Urea as a Potent, Irreversible Myeloperoxidase Inhibitor. J. Pharmacol. Exp. Ther., 367 (1): 147-154. [PMID:30076263]

7. McMillen TS, Heinecke JW, LeBoeuf RC. (2005) Expression of human myeloperoxidase by macrophages promotes atherosclerosis in mice. Circulation, 111 (21): 2798-804. [PMID:15911707]

8. Nussbaum C, Klinke A, Adam M, Baldus S, Sperandio M. (2013) Myeloperoxidase: a leukocyte-derived protagonist of inflammation and cardiovascular disease. Antioxid. Redox Signal., 18 (6): 692-713. [PMID:22823200]

9. Ruggeri RB, Buckbinder L, Bagley SW, Carpino PA, Conn EL, Dowling MS, Fernando DP, Jiao W, Kung DW, Orr ST et al.. (2015) Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases. J. Med. Chem., 58 (21): 8513-28. [PMID:26509551]

10. Soubhye J, Chikh Alard I, Aldib I, Prévost M, Gelbcke M, De Carvalho A, Furtmüller PG, Obinger C, Flemmig J, Tadrent S et al.. (2017) Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure. J. Med. Chem., 60 (15): 6563-6586. [PMID:28671460]

11. Tidén AK, Sjögren T, Svensson M, Bernlind A, Senthilmohan R, Auchère F, Norman H, Markgren PO, Gustavsson S, Schmidt S et al.. (2011) 2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation. J. Biol. Chem., 286 (43): 37578-89. [PMID:21880720]

How to cite this page

1.-.-.- Oxidoreductases: myeloperoxidase. Last modified on 20/08/2018. Accessed on 18/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2789.