Characteristics and mechanism of formation of peroxide-induced heme to protein cross-linking in myoglobin

B. J. Reeder, D. A. Svistunenko, M. A. Sharpe, M. T. Wilson

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

At acidic pH values heme - protein cross-linked myoglobin (Mb-H) forms as a product of a peroxide-induced ferric - ferryl redox cycle. There is evidence that this molecule acts as a marker lor heme - protein-induced oxidative stress in vivo and may exacerbate the severity of oxidative damage due to its enhanced prooxidant and pseudoperoxidatic activities. Therefore, an understanding of its properties and mechanism of formation may be important in understanding the association between heme - proteins and oxidative stress. Although the mechanism of formation of heme - protein cross-linked myoglobin is thought to involve a protein radical (possibly a tyrosine) and the ferryl heme, we show that this hypothesis needs revising. We provide evidence that in addition to a protein-based radical the protonated form of the oxoferryl heme, known to be highly reactive and radical-like in nature, is required to initiate cross-linking. This revised mechanism involves radical/radical termination rather than attack of a single radical onto the porphyrin ring. This proposal better explains the pH dependence of cross-linking and may, in part, explain the therapeutic effectiveness of increasing the pH on myoglobin-induced oxidative stress, e.g., therapy for rhabdomyolysis-associated renal dysfunction.

Original languageEnglish (US)
Pages (from-to)367-375
Number of pages9
JournalBiochemistry
Volume41
Issue number1
DOIs
StatePublished - Jan 8 2002

ASJC Scopus subject areas

  • Biochemistry

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