3ZS1

Human Myeloperoxidase inactivated by TX5

Summary for 3ZS1

• Entry DOI: 10.2210/pdb3zs1/pdb
• Related: 1CXP 1D2V 1D5L 1D7W 1DNU 1DNW 1MHL 1MYP 3ZS0
• Descriptor: MYELOPEROXIDASE LIGHT CHAIN, ACETATE ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (12 entities in total)
• Functional Keywords: oxidoreductase, enzyme inactivation, inflammation, neutrophil, reactive oxygen species (ros), hypochlorous acid
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Lysosome: P05164 P05164
• Total number of polymer chains: 4
• Total formula weight: 137114.53

Authors

Tiden, A.K.,Sjogren, T.,Svensson, M.,Bernlind, A.,Senthilmohan, R.,Auchere, F.,Norman, H.,Markgren, P.O.,Gustavsson, S.,Schmidt, S.,Lundquist, S.,Forbes, L.V.,Magon, N.J.,Jameson, G.N.,Eriksson, H.,Kettle, A.J. (deposition date: 2011-06-21, release date: 2011-08-31, Last modification date: 2024-11-06)

Primary citation

Tiden, A.K.,Sjogren, T.,Svensson, M.,Bernlind, A.,Senthilmohan, R.,Auchere, F.,Norman, H.,Markgren, P.O.,Gustavsson, S.,Schmidt, S.,Lundquist, S.,Forbes, L.V.,Magon, N.J.,Paton, L.N.,Jameson, G.N.,Eriksson, H.,Kettle, A.J.
2-Thioxanthines are Mechanism-Based Inactivators of Myeloperoxidase that Block Oxidative Stress During Inflammation.
J.Biol.Chem., 286:37578-, 2011

PubMed 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.

PubMed: 21880720
DOI: 10.1074/JBC.M111.266981

Experimental method

X-RAY DIFFRACTION (2.6 Å)