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J. Biol. Chem., Vol. 276, Issue 36, 33393-33401, September 7, 2001
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From the Cytokine Research Unit, School of Pathology, University of
New South Wales, Kensington, New South Wales 2052, Australia
Hypochlorite is a major oxidant generated when
neutrophils and macrophages are activated at inflammatory sites, such
as in atherosclerotic lesions. Murine S100A8 (A8) is a major
cytoplasmic protein in neutrophils and is secreted by macrophages in
response to inflammatory stimuli. After incubation with reagent HOCl
for 10 min, ~85% of A8 was converted to 4 oxidation products, with electrospay ionization mass spectrometry masses of
m/z 10354, 10388, 10354 ± 1, and
20707 ± 3. All were resistant to reduction by dithiothreitol.
Initial formation of a reactive Cys sulfenic acid intermediate was
demonstrated by the rapid conjugation of 5,5-dimethyl-1,3-cyclohexanedione (dimedone) to HOCl-treated A8 to form
stable adducts. Matrix-assisted laser desorption-reflectron time of
flight peptide mass fingerprinting of isolated oxidation products
confirmed the mass additions observed in the full-length proteins. Both
Met36/73 were converted to Met36/73
sulfoxides. An additional product with an unusual mass addition of
m/z 14 (±0.2) was identified and corresponded
to the addition of oxygen to Cys41, conjugation to various
Novel Intra- and Inter-molecular Sulfinamide Bonds in S100A8
Produced by Hypochlorite Oxidation*
,
-amines of Lys6, Lys34/35, or
Lys87 with loss of dihydrogen and formation of
stable intra- or inter-molecular sulfinamide cross-links. Specific
fragmentations identified in matrix-assisted laser desorption-post
source decay spectra and low energy collisional-induced dissociation
tandem mass spectroscopy spectra of sulfinamide-containing digest
peptides confirmed Lys34/35 to Cys41
sulfinamide bonds. HOCl oxidation of mutants lacking Cys41
(Ala41S100A8) or specific Lys residues (e.g.
Lys34/35, Ala34/35S100A8) did not form
sulfinamide cross-links. HOCl generated by myeloperoxidase and
H2O2 and by phorbol 12-myristate
13-acetate-activated neutrophils also formed these
products. In contrast to the disulfide-linked dimer,
oxidized monomer retained normal chemotactic activity for neutrophils.
Sulfinamide bond formation represents a novel oxidative cross-linking
process between thiols and amines and may be a general consequence of
HOCl protein oxidation in inflammation not identified previously.
Similar modifications in other proteins could potentially regulate
normal and pathological processes during aging, atherogenesis, fibrosis, and neurogenerative diseases.
*
This work was supported in part by grants from the National
Health and Medical Research Council of Australia and Australian Research Council.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. Tel.: 61-2-9385-1599;
Fax: 61-2-9385-1389; E-mail: m.raftery@unsw.edu.au.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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