Topography of tyrosine residues and their involvement in peroxidation of polyunsaturated cardiolipin in cytochrome c/cardiolipin peroxidase complexes

Details

• Alternative Title:
  Biochim Biophys Acta
• Personal Author:
  Kapralov, Alexandr A. ; Yanamala, Naveena ; Tyurina, Yulia Y. ; Castro, Laura ; Arias, Alejandro Samhan ; Vladimirov, Yuri A. ; Maeda, Akihiro ; Weitz, Andrew A. ; Peterson, Jim ; Mylnikov, Danila ; Demicheli, Verónica ; Tortora, Verónica ; Klein-Seetharaman, Judith ; Radi, Rafael ; Kagan, Valerian E.
• Description:
  Formation of cytochrome c (cyt c)/cardiolipin (CL) peroxidase complex selective toward peroxidation of polyunsaturated CLs is a pre-requisite for mitochondrial membrane permeabilization. Tyrosine residues - via the generation of tyrosyl radicals (Tyr) - are likely reactive intermediates of the peroxidase cycle leading to CL peroxidation. We used mutants of horse heart cyt c in which each of the four Tyr residues was substituted for Phe and assessed their contribution to the peroxidase catalysis. Tyr67Phe mutation was associated with a partial loss of the oxygenase function of the cyt c/CL complex and the lowest concentration of H(2)O(2)-induced Tyr radicals in electron paramagnetic resonance (EPR) spectra. Our MS experiments directly demonstrated decreased production of CL-hydroperoxides (CL-OOH) by Tyr67Phe mutant. Similarly, oxidation of a phenolic substrate, Amplex Red, was affected to a greater extent in Tyr67Phe than in three other mutants. Tyr67Phe mutant exerted high resistance to H(2)O(2)-induced oligomerization. Measurements of Tyr fluorescence, hetero-nuclear magnetic resonance (NMR) and computer simulations position Tyr67 in close proximity to the porphyrin ring heme iron and one of the two axial heme-iron ligand residues, Met80. Thus, the highly conserved Tyr67 is a likely electron-donor (radical acceptor) in the oxygenase half-reaction of the cyt c/CL peroxidase complex.
• Subjects:
  Animals Cardiolipins Computer Simulation Cytochromes C Electron Spin Resonance Spectroscopy Heme Horses Hydrogen Peroxide Iron Magnetic Resonance Spectroscopy Mitochondrial Membranes Mutation Myocardium Oxygen Oxygenases Peroxidase Peroxidases Phenylalanine Tyrosine

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• Source:
  Biochim Biophys Acta. 2011; 1808(9):2147-2155.
• Pubmed ID:
  21550335
• Pubmed Central ID:
  PMC3321730
• Document Type:
  Journal Article
• Funding:
  R01 HL070755/HL/NHLBI NIH HHS/United States ; R01 HL070755-08/HL/NHLBI NIH HHS/United States ; R01 OH008282/OH/NIOSH CDC HHS/United States ; U19 AI068021/AI/NIAID NIH HHS/United States ; U19AIO68021/PHS HHS/United States ; HL094488/HL/NHLBI NIH HHS/United States ; R01 HL094488-02/HL/NHLBI NIH HHS/United States ; R01 HL094488/HL/NHLBI NIH HHS/United States ; OH008282/OH/NIOSH CDC HHS/United States ; Howard Hughes Medical Institute/United States ; HL70755/HL/NHLBI NIH HHS/United States
• Volume:
  1808
• Issue:
  9
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0d9aec68edead9653782ad53fb43d74582eb4e5f37afa0b66ab65cf3a32f90ea
• Download URL:
  https://stacks.cdc.gov/view/cdc/33336/cdc_33336_DS1.pdf
• File Type:
  [PDF - 1.75 MB ]