Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids

Details

• Personal Author:
  Amoscato AA ; Atkinson J ; Bahar I ; Bakan A ; Bayir H ; Garapati VK ; Huang Z ; Jiang J ; Kagan VE ; Kapralov AA ; Peterson J ; Saxena S ; Silva KI
• Description:
  Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency. [Description provided by NIOSH]
• Subjects:
  Animals Chemistry Cytology Energy Metabolism Free Radicals Laboratories Occupational Health Organophosphates Radiation Safety
• Keywords:
  Author Keywords: All-atom Molecular Dynamics Simulation Cardiolipin Peroxidation Cell-damage Cell-function Cellular-reactions Chemical-composition Chemical-properties Cytochrome C Drugs Electron Paramagnetic Resonance Enzymology Free Radicals Imidazole-substituted Stearic Acid Laboratory-animals Metabolism Mitochondria Targeting Organo-phosphorus-compounds Oxidation Peroxidase Inhibitors Pharmacology Radiation-effects Reactive Intermediates

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• ISSN:
  0891-5849
• 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
• Pages in Document:
  221-230
• Volume:
  71
• NIOSHTIC Number:
  nn:20045511
• Citation:
  Free Radic Biol Med 2014 Jun; 71:221-230
• Contact Point Address:
  Valerian E. Kagan, Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219
• Email:
  kagan@pitt.edu
• Federal Fiscal Year:
  2014
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Free Radical Biology and Medicine
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4c7a87ebbad22b5dde1f785c6cdfa4490b370f5db0faf63152b53a023f66c4661e6d0b93305d9c7edd79e813a1b1e830725ee530679ff7134c47e1e3bfa5c1ef
• Download URL:
  https://stacks.cdc.gov/view/cdc/200906/cdc_200906_DS1.pdf
• File Type:
  [PDF - 3.92 MB ]