Molecular Design of New Inhibitors of Peroxidase Activity of Cytochrome c/Cardiolipin Complexes: Fluorescent Oxadiazole-Derivatized Cardiolipin

Interaction of a mitochondria-specific anionic phospholipid, cardiolipin (CL), with an intermembrane protein, cytochrome c (cyt c), yields a peroxidase complex. During apoptosis, the complex induces accumulation of CL oxidation products that are essential for detachment of cyt c from the mitochondri...

Full description

Saved in:
Bibliographic Details
Published in:Biochemistry (Easton) 2008-12, Vol.47 (51), p.13699-13710
Main Authors: Borisenko, G. G, Kapralov, A. A, Tyurin, V. A, Maeda, A, Stoyanovsky, D. A, Kagan, V. E
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cardiolipins - chemistry
Chemistry, Pharmaceutical - methods
Cytochromes c - metabolism
Drug Design
Fluorescent Dyes - pharmacology
Horses
Humans
Liposomes - chemistry
Myocardium - metabolism
Oxadiazoles - chemistry
Peroxidases - chemistry
Spectrometry, Fluorescence - methods
Spectrometry, Mass, Electrospray Ionization
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Interaction of a mitochondria-specific anionic phospholipid, cardiolipin (CL), with an intermembrane protein, cytochrome c (cyt c), yields a peroxidase complex. During apoptosis, the complex induces accumulation of CL oxidation products that are essential for detachment of cyt c from the mitochondrial membrane, induction of permeability transition, and release of proapoptotic factors into the cytosol. Therefore, suppression of the peroxidase activity and prevention of CL oxidation may lead to discovery of new antiapoptotic drugs. Here, we report a new approach to regulate the cyt c peroxidase activity by using modified CL with an oxidizable and fluorescent 7-nitro-2,1,3-benzoxadiazole (NBD) moiety (NBD-CL). We demonstrate that NBD-CL forms high-affinity complexes with cyt c and blocks cyt c-catalyzed oxidation of several peroxidase substrates, cyt c self-oxidation, and, most importantly, inhibits cyt c-dependent oxidation of polyunsaturated tetralinoleoyl CL (TLCL) and accumulation of TLCL hydroperoxides. Electrospray ionization mass spectrometry and fluorescence analysis revealed that oxidation and cleavage of the NBD moiety of NBD-CL underlie the inhibition mechanism. We conclude that modified CL combining a nonoxidizable monounsaturated trioleoyl CL with a C12-NBD fragment undergoes a regiospecific oxidation thereby representing a novel inhibitor of cyt c peroxidase activity.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi801507s