Structural re-arrangement and peroxidase activation of cytochrome c by anionic analogues of vitamin E, tocopherol succinate and tocopherol phosphate

Details

• Personal Author:
  Djukic M ; Kagan VE ; Kapralov AA ; Klein-Seetharaman J ; Mao G ; Neuzil J ; Peterson J ; Stoyanovsky DA ; Stursa J ; Yanamala N
• Description:
  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, a-tocopherol succinate (a-TOS) and a-tocopherol phosphate (a-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 a-TOS and a-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with a-TOS and tBOOH. A mitochondria-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 a-TOS may contribute to its known anti-cancer pharmacological activity. [Description provided by NIOSH]
• Subjects:
  Animals Energy Metabolism Genetics Laboratories Occupational Health Safety
• Keywords:
  Author Keywords: Cancer Therapy Computer Modeling Cytochrome C Drugs Hemoproteins Laboratory-animals Metabolism Models Peroxidase Pharmacology Protein Folding Proteins Vitamin E

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• ISSN:
  0021-9258
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  289
• Issue:
  47
• NIOSHTIC Number:
  nn:20045745
• Citation:
  J Biol Chem 2014 Nov; 289(47):32488-32498
• Contact Point Address:
  Valerian E. Kagan, Center for Free Radical and Antioxidant Health, Dept. of Environmental and Occupational Health, University of Pittsburgh, Bridgeside Point 100 Technology Drive, Suite 350, Pittsburgh, PA 15219
• Email:
  kagan@pitt.edu
• Federal Fiscal Year:
  2015
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Journal of Biological Chemistry
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7200d45d2a01c77960566949114f90f6ead33e06e64f6e24eb2295619342ec9c364b5c71cf007844e960aadfb9ad3fbd48863eab7834f813fdad6c76ba88e294
• Download URL:
  https://stacks.cdc.gov/view/cdc/201044/cdc_201044_DS1.pdf
• File Type:
  [PDF - 1.42 MB ]