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2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation.

Tidén AK, Sjögren T, Svensson M, Bernlind A, Senthilmohan R, Auchère 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 286 37578-89 (2011)
Cited: 77 times
EuropePMC logo PMID: 21880720

Abstract

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.

Reviews citing this publication (21)

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Articles citing this publication (56)

  1. Requirements for NADPH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus. Parker H, Dragunow M, Hampton MB, Kettle AJ, Winterbourn CC. J Leukoc Biol 92 841-849 (2012)
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  13. Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease. Chandler JD, Margaroli C, Horati H, Kilgore MB, Veltman M, Liu HK, Taurone AJ, Peng L, Guglani L, Uppal K, Go YM, Tiddens HAWM, Scholte BJ, Tirouvanziam R, Jones DP, Janssens HM. Eur Respir J 52 1801118 (2018)
  14. Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice. Lehners A, Lange S, Niemann G, Rosendahl A, Meyer-Schwesinger C, Oh J, Stahl R, Ehmke H, Benndorf R, Klinke A, Baldus S, Wenzel UO. Am J Physiol Renal Physiol 307 F407-17 (2014)
  15. Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN. Antonelou M, Michaëlsson E, Evans RDR, Wang CJ, Henderson SR, Walker LSK, Unwin RJ, Salama AD, RAVE-ITN Investigators. J Am Soc Nephrol 31 350-364 (2020)
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  17. Exposure of Pseudomonas aeruginosa to bactericidal hypochlorous acid during neutrophil phagocytosis is compromised in cystic fibrosis. Dickerhof N, Isles V, Pattemore P, Hampton MB, Kettle AJ. J Biol Chem 294 13502-13514 (2019)
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  21. Characterization and antioxidant properties of six Algerian propolis extracts: ethyl acetate extracts inhibit myeloperoxidase activity. Boufadi YM, Soubhye J, Riazi A, Rousseau A, Vanhaeverbeek M, Nève J, Boudjeltia KZ, Van Antwerpen P. Int J Mol Sci 15 2327-2345 (2014)
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  23. Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes. Ramachandra CJA, Kp MMJ, Chua J, Hernandez-Resendiz S, Liehn EA, Knöll R, Gan LM, Michaëlsson E, Jonsson MKB, Ryden-Markinhuhta K, Bhat RV, Fritsche-Danielson R, Lin YH, Sadayappan S, Tang HC, Wong P, Shim W, Hausenloy DJ. Cardiovasc Res 118 517-530 (2022)
  24. Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy. Atwal M, Lishman EL, Austin CA, Cowell IG. Mol Pharmacol 91 49-57 (2017)
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