3zs0

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Human Myeloperoxidase inactivated by TX2

Structural highlights

3zs0 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:ACT, BMA, CA, CL, CSO, FUC, HEM, MAN, NAG, SO4, ZS0
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PERM_HUMAN Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:254600. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.[1] [2] [3] [4] [5]

Function

PERM_HUMAN Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity.

Publication Abstract from PubMed

Myeloperoxidase (MPO) is a prime candidate for promoting oxidative stress during inflammation. This abundant enzyme of neutrophils uses hydrogen peroxide to oxidize chloride to highly reactive and toxic chlorine bleach. We have identified 2-thioxanthines as potent mechanism-based inactivators of MPO. Mass spectrometry and x-ray crystal structures revealed that these inhibitors become covalently attached to the heme prosthetic groups of the enzyme. We propose a mechanism whereby 2-thioxanthines are oxidized, and their incipient free radicals react with the heme groups of the enzyme before they can exit the active site. 2-Thioxanthines inhibited MPO in plasma and decreased protein chlorination in a mouse model of peritonitis. They slowed but did not prevent neutrophils from killing bacteria and were poor inhibitors of thyroid peroxidase. Our study shows that MPO is susceptible to the free radicals it generates, and this Achilles' heel of the enzyme can be exploited to block oxidative stress during inflammation.

2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation.,Tiden AK, Sjogren T, Svensson M, Bernlind A, Senthilmohan R, Auchere F, Norman H, Markgren PO, Gustavsson S, Schmidt S, Lundquist S, Forbes LV, Magon NJ, Paton LN, Jameson GN, Eriksson H, Kettle AJ J Biol Chem. 2011 Oct 28;286(43):37578-89. Epub 2011 Aug 31. PMID:21880720[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
22 reviews cite this structure
Reactive Oxygen Species and Neutrophil Function.
Winterbourn et al. (2016)
21 more
59 other articles
No citations found

See Also

References

  1. ↑ Kizaki M, Miller CW, Selsted ME, Koeffler HP. Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency. Blood. 1994 Apr 1;83(7):1935-40. PMID:8142659
  2. ↑ Nauseef WM, Brigham S, Cogley M. Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan. J Biol Chem. 1994 Jan 14;269(2):1212-6. PMID:7904599
  3. ↑ Nauseef WM, Cogley M, McCormick S. Effect of the R569W missense mutation on the biosynthesis of myeloperoxidase. J Biol Chem. 1996 Apr 19;271(16):9546-9. PMID:8621627
  4. ↑ DeLeo FR, Goedken M, McCormick SJ, Nauseef WM. A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. J Clin Invest. 1998 Jun 15;101(12):2900-9. PMID:9637725 doi:10.1172/JCI2649
  5. ↑ Romano M, Dri P, Dadalt L, Patriarca P, Baralle FE. Biochemical and molecular characterization of hereditary myeloperoxidase deficiency. Blood. 1997 Nov 15;90(10):4126-34. PMID:9354683
  6. ↑ Tiden AK, Sjogren T, Svensson M, Bernlind A, Senthilmohan R, Auchere F, Norman H, Markgren PO, Gustavsson S, Schmidt S, Lundquist S, Forbes LV, Magon NJ, Paton LN, Jameson GN, Eriksson H, Kettle AJ. 2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation. J Biol Chem. 2011 Oct 28;286(43):37578-89. Epub 2011 Aug 31. PMID:21880720 doi:10.1074/jbc.M111.266981

Contents


PDB ID 3zs0

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OCA

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