Format

Send to

Choose Destination
See comment in PubMed Commons below
Free Radic Biol Med. 2014 Jun;71:221-30. doi: 10.1016/j.freeradbiomed.2014.02.029. Epub 2014 Mar 12.

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

Author information

1
Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
2
Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA.
3
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15219, USA.
4
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
5
Department of Chemistry & Centre for Biotechnology, Brock University, St. Catharines, ON L2S 3A1, Canada.
6
Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
7
Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Pharmacology and Chemical Biology, and University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: kagan@pitt.edu.

Abstract

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.

KEYWORDS:

All-atom molecular dynamics simulation; Cardiolipin peroxidation; Cytochrome c; Electron paramagnetic resonance; Free radicals; Imidazole-substituted stearic acid; Mitochondria targeting; Peroxidase inhibitors; Reactive intermediates

[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center