Cytochrome c: A catalyst and target of nitrite-hydrogen peroxide-dependent protein nitration

Laura Castro, Jason P. Eiserich, Scott Sweeney, Rafael Radi, Bruce A. Freeman

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Nitration of protein tyrosine residues to 3-nitrotyrosine (NO 2Tyr) serves as both a marker and mediator of pathogenic reactions of nitric oxide (.NO), with peroxynitrite (ONOO-) and leukocyte peroxidase-derived nitrogen dioxide (.NO2) being proximal mediators of nitration reactions in vivo. Cytochrome c is a respiratory and apoptotic signaling heme protein localized exofacially on the inner mitochondrial membrane. We report herein a novel function for cytochrome c as a catalyst for nitrite (NO2 -) and hydrogen peroxide (H2O2)-mediated nitration reactions. Cytochrome c catalyzes both self- and adjacent-molecule (hydroxyphenylacetic acid, Mn-superoxide dismutase) nitration via heme-dependent mechanisms involving tyrosyl radical and .NO2 production, as for phagocyte peroxidases. Although low molecular weight phenolic nitration yields were similar for cytochrome c and the proteolytic fragment of cytochrome c microperoxidase-11 (MPx-11), greater extents of protein nitration occurred when MPx-11 served as catalyst. Partial proteolysis of cytochrome c increased both the peroxidase and nitrating activities of cytochrome c. Extensive tyrosine nitration of Mn-superoxide dismutase occurred when exposed to either cytochrome c or MPx-11 in the presence of H2O2 and NO 2 -, with no apparent decrease in catalytic activity. These results reveal a post-translational tyrosine modification mechanism that is mediated by an abundant hemoprotein present in both mitochondrial and cytosolic compartments. The data also infer that the distribution of specific proteins capable of serving as potent catalysts of nitration can lend both spatial and molecular specificity to biomolecule nitration reactions.

Original languageEnglish (US)
Pages (from-to)99-107
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume421
Issue number1
DOIs
StatePublished - Jan 1 2004

Fingerprint

Nitration
Nitrites
Cytochromes c
Hydrogen Peroxide
Catalysts
Proteins
Tyrosine
Peroxidase
Superoxide Dismutase
Hemeproteins
Nitrogen Dioxide
Peroxidases
Proteolysis
Peroxynitrous Acid
Mitochondrial Membranes
Post Translational Protein Processing
Phagocytes
Heme
Biomolecules
Nitric Oxide

Keywords

  • Cytochrome c
  • Hydrogen peroxide
  • Manganese superoxide dismutase
  • Mitochondria
  • Nitric oxide
  • Nitrite
  • Peroxidase
  • Peroxynitrite

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Cytochrome c : A catalyst and target of nitrite-hydrogen peroxide-dependent protein nitration. / Castro, Laura; Eiserich, Jason P.; Sweeney, Scott; Radi, Rafael; Freeman, Bruce A.

In: Archives of Biochemistry and Biophysics, Vol. 421, No. 1, 01.01.2004, p. 99-107.

Research output: Contribution to journalArticle

Castro, Laura ; Eiserich, Jason P. ; Sweeney, Scott ; Radi, Rafael ; Freeman, Bruce A. / Cytochrome c : A catalyst and target of nitrite-hydrogen peroxide-dependent protein nitration. In: Archives of Biochemistry and Biophysics. 2004 ; Vol. 421, No. 1. pp. 99-107.
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