title: 2-thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation.
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.
authors: AstraZeneca R&D, Södertälje SE-151 85, Sweden.
authors: Anna-Karin
authors: AK
authors: Tidén
authors: Tove
authors: T
authors: Sjögren
authors: Mats
authors: M
authors: Svensson
authors: Alexandra
authors: A
authors: Bernlind
authors: Revathy
authors: R
authors: Senthilmohan
authors: Francoise
authors: F
authors: Auchère
authors: Henrietta
authors: H
authors: Norman
authors: Per-Olof
authors: PO
authors: Markgren
authors: Susanne
authors: S
authors: Gustavsson
authors: Staffan
authors: S
authors: Schmidt
authors: Stefan
authors: S
authors: Lundquist
authors: Louisa V
authors: LV
authors: Forbes
authors: Nicholas J
authors: NJ
authors: Magon
authors: Louise N
authors: LN
authors: Paton
authors: Guy N L
authors: GN
authors: Jameson
authors: Håkan
authors: H
authors: Eriksson
authors: Anthony J
authors: AJ
authors: Kettle
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000208:ethnology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010538:Peritonitis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014970:Xanthines; D009195:Peroxidase