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Peroxidase activity and structural transitions of cytochrome c bound to cardiolipin-containing membranes.

Authors
Belikova-NA; Vladimirov-YA; Osipov-AN; Kapralov-AA; Tyurin-VA; Potapovich-MV; Basova-LV; Peterson-J; Kurnikov-IV; Kagan-VE
Source
Biochemistry 2006 Apr; 45(15):4998-5009
NIOSHTIC No.
20030273
Abstract
During apoptosis, cytochrome c (cyt c) is released from intermembrane space of mitochondria into the cytosol where it triggers the caspase-dependent machinery. We discovered that cyt c plays another critical role in early apoptosis as a cardiolipin (CL)-specific oxygenase to produce CL hydroperoxides required for release of pro-apoptotic factors [Kagan, V. E., et al. (2005) Nat. Chem. Biol. 1, 223-232]. We quantitatively characterized the activation of peroxidase activity of cyt c by CL and hydrogen peroxide. At low ionic strength and high CL/cyt c ratios, peroxidase activity of the CL/cyt c complex was increased >50 times. This catalytic activity correlated with partial unfolding of cyt c monitored by Trp(59) fluorescence and absorbance at 695 nm (Fe-S(Met(80)) band). The peroxidase activity increase preceded the loss of protein tertiary structure. Monounsaturated tetraoleoyl-CL (TOCL) induced peroxidase activity and unfolding of cyt c more effectively than saturated tetramyristoyl-CL (TMCL). TOCL/cyt c complex was found more resistant to dissociation by high salt concentration. These findings suggest that electrostatic CL/cyt c interactions are central to the initiation of the peroxidase activity, while hydrophobic interactions are involved when cyt c's tertiary structure is lost. In the presence of CL, cyt c peroxidase activity is activated at lower H(2)O(2) concentrations than for isolated cyt c molecules. This suggests that redistribution of CL in the mitochondrial membranes combined with increased production of H(2)O(2) can switch on the peroxidase activity of cyt c and CL oxidation in mitochondria-a required step in execution of apoptosis.
Keywords
Metabolism; Pharmacology; Cell-metabolism; Enzymes; Enzyme-activity; Lipids; Lipid-peroxidation; Oxidation-reduction-reactions; Oxidation
Contact
Center for Free Radical and Antioxidant Health and Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219-3130, USA
CODEN
BICHAW
CAS No.
9007-43-6; 73-22-3; 65-61-2; 33419-42-0; 106070-31-9; 10015-85-7
Publication Date
20060418
Document Type
Journal Article
Funding Type
Grant
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008282
Issue of Publication
15
ISSN
0006-2960
Source Name
Biochemistry
State
PA
Performing Organization
University of Pittsburgh at Pittsburgh
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