Abstract
Salicylhydroxamic and benzohydroxamic acids were found to bind to the resting state of myeloperoxidase and inhibit ligand binding to the heme iron. An ionizable group on the enzyme with pKa = 4 affects salicylhydroxamic acid binding; binding occurs when this group is not protonated. The binding of the heme iron ligands (e.g. cyanide, nitrite, and chloride) is probably controlled by the same ionizable group. The equilibrium dissociation constant of the salicylhydroxamic acid-myeloperoxidase complex is about 2 x 10(-6) M, and the association rate constant is 7.4 x 10(6) M-1.s-1. Salicylhydroxamic acid serves as a donor to the higher oxidation state of myeloperoxidase and thereby inhibits guaiacol oxidation. Salicylhydroxamic acid was also found to bind to intestinal peroxidase and lactoperoxidase. Salicylhydroxamic acid binding to all three mammalian peroxidases was about 3 orders of magnitude stronger than benzohydroxamic acid binding. We conclude that the salicylhydroxamic and benzohydroxamic acids bind in the distal heme cavity of these peroxidases and interact with the heme ligand binding site.
Highlights
Salicylhydroxamic and benzohydroxamicacids were found to bind to the resting state of myeloperoxidase and inhibit ligand binding to the heme iron
Salicylhydroxamic acid serves as a donor to the higher oxidation state of myeloperoxidase and thereby inhibciation constant for the enzyme-chloride complex, and dissociation constantof the enzyme-cyanide complex (Ikeda-Saito, 1985)
Salicylhydroxamic acid binding to all three et al, 1990) demonstrates unequivocally the presence of the mammalian peroxidases was about 3 orders of magni- protonated distal histidineresidue in the cyanide complex of tude stronger than benzohydroxamicacid binding
Summary
Salicylhydroxamic acid serves as a donor to the higher oxidation state of myeloperoxidase and thereby inhibciation constant for the enzyme-chloride complex, and dissociation constantof the enzyme-cyanide complex (Ikeda-Saito, 1985). The chemical structures of these hydroxamic acids differ only at position 2 of the benzenering,where SHAhas hydroxyl andBHA hydrogen (Fig. 1).We found that (i) both hydroxamic acids bind to the resting state of MPO when an ionizable group with a pK, value of 4 on the enzyme is not protonated (ii) both acids inhibit binding of small molecules such as nitrite and chloride to the heme irofnthe enzyme; (iii) SHA binds to the resting enzyme about 3 orders of magnitude stronger. EXPERIMENTALPROCEDURES Bovine granulocyte MPO, bovine milk lactoperoxidase, and hog zohydroxamic acid SHA, salicylhydroxamic acid
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