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J. Biol. Chem., Vol. 276, Issue 1, 215-224, January 5, 2001
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From the Departments of Although the pseudohalide thiocyanate
(SCN
Eosinophil Peroxidase Oxidation of Thiocyanate
CHARACTERIZATION OF MAJOR REACTION PRODUCTS AND A POTENTIAL
SULFHYDRYL-TARGETED CYTOTOXICITY SYSTEM*
,,
,
Internal Medicine and
§ Biochemistry and the ¶ University of Minnesota Cancer
Center, University of Minnesota Medical School, Minneapolis, Minnesota
55455 and Departments of Cell Biology and ** Cardiology,
Cleveland Clinic Foundation, Cleveland, Ohio 44195
) is the preferred substrate for eosinophil
peroxidase (EPO) in fluids of physiologic halide composition, the
product(s) of this reaction have not been directly identified, and
mechanisms underlying their cytotoxic potential are poorly
characterized. We used nuclear magnetic resonance spectroscopy (NMR),
electrospray ionization mass spectrometry, and quantitative chemical
analysis to identify the principal reaction products of both the
EPO/SCN/H2O2 system and activated
eosinophils as roughly equimolar amounts of OSCN
(hypothiocyanite) and OCN (cyanate). Red blood cells
exposed to increasing concentrations of
OSCN/OCN are first depleted of glutathione,
after which glutathione S-transferase and
glyceraldehyde-3-phosphate dehydrogenase then ATPases undergo sulfhydryl (SH) reductant-reversible inactivation before lysing. OSCN/OCN inactivates red blood cell
membrane ATPases 10-1000 times more potently than do HOCl, HOBr, and
H2O2. Exposure of glutathione S-transferase to
[14C]OSCN/OCN causes SH
reductant-reversible disulfide bonding and covalent isotope labeling.
We propose that EPO/SCN/H2O2
reaction products comprise a potential SH-targeted cytotoxic system
that functions in striking contrast to HOCl, the highly but relatively
indiscriminantly reactive product of the neutrophil myeloperoxidase system.
*
This work was supported by National Institutes of Health
Grants RO-1-HL48915 (to A. S.) and HL 61878 (to S. L. H.). Some of the mass spectrometry studies were performed at the Cleveland Clinic
Foundation Mass Spectrometry Facility.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Box 480 FUMC,
University of Minnesota, Minneapolis, MN 55455. Tel.: 612-624-9410; Fax: 612-625-6919; E-mail: slung001@ tc.umn.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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