Structural Re-arrangement and Peroxidase Activation of Cytochrome c by Anionic Analogues of Vitamin E, Tocopherol Succinate and Tocopherol Phosphate

0444273 - BTÚ 2016 RIV US eng J - Journal Article
Yanamala, N. - Kapralov, A.A. - Djukic, M. - Peterson, J. - Mao, G. - Klein-Seetharaman, J. - Stoyanovsky, D.A. - Stursa, J. - Neužil, Jiří - Kagan, V.E.
Structural Re-arrangement and Peroxidase Activation of Cytochrome c by Anionic Analogues of Vitamin E, Tocopherol Succinate and Tocopherol Phosphate.
Journal of Biological Chemistry. Roč. 289, č. 47 (2014). ISSN 0021-9258. E-ISSN 1083-351X
R&D Projects: GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : CARDIOLIPIN-CONTAINING MEMBRANES * CELL-DEATH * MOLECULAR-MECHANISM
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 4.573, year: 2014

Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, alpha-tocopherol succinate (alpha-TOS) and alpha-tocopherol phosphate (alpha-TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met(80)) bond associated with unfolding of cytochrome c. We found that alpha-TOS and alpha-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with alpha-TOS and tBOOH. Amitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c(+/+) cells than in cytochrome c(-/-) cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by alpha-TOS may contribute to its known anti-cancer pharmacological activity
Permanent Link: http://hdl.handle.net/11104/0246915