The long-term goal of this project is to determine the mechanism of peroxidation catalysis for members of a homologous family of mammalian peroxidases. Myeloperoxidase, located in the azurophil granules of neutrophils, catalyses the oxidation of chloride ion to hypochlorite which is effective in killing bacteria, viruses and fungi. It also aggravates tissue damage in emphysema through its activation of human alpha-1 antiproteinase and inhibitors of this enzyme have particular clinical relevance since they may be useful in reducing tissue damage in a variety of inflammatory diseases. Protective functions are associated with related peroxidases found in milk, saliva and the intestinal mucosa. In contrast, thyroid peroxidase participates in the biosynthesis of the hormone thyroxine by catalyzing the iodination and coupling of tyrosines. The x-ray crystal structure of human myeloperoxidase has recently been determined at 2.25 A resolution and it will be extended to 2 A or better using data collected at cryogenic temperatures. This high-resolution structure will then be used for the x-ray studies of cyanide and halide ion binding to the enzyme and of the complexes of the enzyme with aromatic hydrazine and hydrazide inhibitors. These studies are designed to provide new information on the mechanism of catalysis for both two electron oxidation of halides and one electron oxidation of aromatic substrates. Conditions will be investigated for crystallization of lactoperoxidase in a form suitable for x-ray analysis. Unlike myeloperoxidase, this enzyme cannot oxidise chloride ion and is thought to have a different mode of attachment of the heme to the polypeptide chain. It is hoped that comparison of the conformations of the heme environments of these two enzymes will lead to an understanding of their structural and functional differences.
| Hori, H; Fenna, R E; Kimura, S et al. (1994) Aromatic substrate molecules bind at the distal heme pocket of myeloperoxidase. J Biol Chem 269:8388-92 |
