Urate as a physiological substrate for myeloperoxidase: implications for hyperuricemia and inflammation.
Urate and myeloperoxidase (MPO) are associated with adverse outcomes in cardiovascular disease. In this study, we assessed whether urate is a likely physiological substrate for MPO and if the products of their interaction have the potential to exacerbate inflammation. Urate was readily oxidized by MPO and hydrogen peroxide to 5-hydroxyisourate, which decayed to predominantly allantoin. The redox intermediates of MPO were reduced by urate with rate constants of 4.6 × 10(5) M(-1) s(-1) for compound I and 1.7 × 10(4) M(-1) s(-1) for compound II. Urate competed with chloride for oxidation by MPO and at hyperuricemic levels is expected to be a substantive substrate for the enzyme. Oxidation of urate promoted super-stoichiometric consumption of glutathione, which indicates that it is converted to a free radical intermediate. In combination with superoxide and hydrogen peroxide, MPO oxidized urate to a reactive hydroperoxide. This would form by addition of superoxide to the urate radical. Urate also enhanced MPO-dependent consumption of nitric oxide. In human plasma, stimulated neutrophils produced allantoin in a reaction dependent on the NADPH oxidase, MPO and superoxide. We propose that urate is a physiological substrate for MPO that is oxidized to the urate radical. The reactions of this radical with superoxide and nitric oxide provide a plausible link between urate and MPO in cardiovascular disease.
Free Radical Research Group, Department of Pathology, University of Otago, P. O. Box 4345, 8140 Christchurch, New Zealand.
Flavia C
FC
Meotti
Guy N L
GN
Jameson
Rufus
R
Turner
D Tim
DT
Harwood
Samantha
S
Stockwell
Martin D
MD
Rees
Shane R
SR
Thomas
Anthony J
AJ
Kettle
D000481:Allantoin / Q000096:biosynthesis / Q000737:chemistry; D002318:Cardiovascular Diseases / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism*; D033461:Hyperuricemia / Q000201:enzymology*; D007249:Inflammation; D019255:NADPH Oxidases / Q000737:chemistry / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism*; D014527:Uric Acid
D013481:Superoxides; D014527:Uric Acid; D000481:Allantoin; D006861:Hydrogen Peroxide; D009195:Peroxidase; D019255:NADPH Oxidases
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