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J. Biol. Chem., Vol. 281, Issue 52, 39860-39869, December 29, 2006

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Modeling the Reactions of Superoxide and Myeloperoxidase in the Neutrophil Phagosome

IMPLICATIONS FOR MICROBIAL KILLING^*

Christine C. Winterbourn¹, Mark B. Hampton, John H Livesey, and Anthony J. Kettle

From the Department of Pathology, Christchurch School of Medicine and Health Sciences, P. O. Box 4345, Christchurch and the Department of Endocrinology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand

Neutrophils kill bacteria by ingesting them into phagosomes where superoxide and cytoplasmic granule constituents, including myeloperoxidase, are released. Myeloperoxidase converts chloride and hydrogen peroxide to hypochlorous acid (HOCl), which is strongly microbicidal. However, the role of oxidants in killing and the species responsible are poorly understood and the subject of current debate. To assess what oxidative mechanisms are likely to operate in the narrow confines of the phagosome, we have used a kinetic model to examine the fate of superoxide and its interactions with myeloperoxidase. Known rate constants for reactions of myeloperoxidase have been used and substrate concentrations estimated from neutrophil morphology. In the model, superoxide is generated at several mM/s. Most react with myeloperoxidase, which is present at millimolar concentrations, and rapidly convert the enzyme to compound III. Compound III turnover by superoxide is essential to maintain enzyme activity. Superoxide stabilizes at 25 µM and hydrogen peroxide in the low micromolar range. HOCl production is efficient if there is adequate chloride supply, but further knowledge on chloride concentrations and transport mechanisms is needed to assess whether this is the case. Low myeloperoxidase concentrations also limit HOCl production by allowing more hydrogen peroxide to escape from the phagosome. In the absence of myeloperoxidase, superoxide increases to >100 µM but hydrogen peroxide to only 30 µM. Most of the HOCl reacts with released granule proteins before reaching the bacterium, and chloramine products may be effectors of its antimicrobial activity. Hydroxyl radicals should form only after all susceptible protein targets are consumed.

Received for publication, June 20, 2006 , and in revised form, September 12, 2006.

^* This work was supported by the Health Research Council of New Zealand. This work was presented in part at a conference on The Peroxidase Multigene Family of Enzymes (80). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 64-3-3640564; Fax: 64-3-364-1083; E-mail: christine.winterbourn{at}chmeds.ac.nz.

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