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11 February 2008 Protein oxidation by the phthalocyanine photosensitizer Pc 4 and light: detection of a unique singlet oxygen-generated product in cytochrome c
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Abstract
Photodynamic Therapy (PDT) damages cells and tissues via generation of singlet oxygen (1O2). One target of 1O2 in biological systems may be proteins, and numerous studies have shown that 1O2 can inactivate enzymes. Whereas the reactions of 1O2 with His, Tyr, Met, Cys, and Trp are well known, the reaction with these same residues in proteins is less well studied. PDT induces apoptosis via the release of cytochrome c (Cyt-c) from mitochondria into the cytosol, followed by activation of caspases. Because Cyt-c resides in the mitochondrial intermembrane space, associated with the inner membrane, it would be exposed to 1O2 generated by photoactivation of lipophilic photosensitizers like Pc 4 located in mitochondrial membranes. Studies by others have shown that 1O2 can oxidize the ferro-form of Cyt-c, inactivate the function of Cyt-c as an electron carrier, and result in the loss of His, Trp, Tyr, and Met residues. However, mass spectrometric evidence for modifications of specific amino acid side chains of proteins by 1O2 has not been reported to our knowledge. Here, we used MALDI-TOF-MS and LC-ESI-MS to study the reaction of 1O2 with amino acid residues within two model peptides in homogeneous medium and within Cyt-c in homogeneous media and in liposomes. The analyses revealed multiple oxidation products, including at least one His-derived product that is unique to singlet oxygen and not found following reaction with other reactive oxygen species. This product may serve as a marker of mitochondrial photodynamic damage.
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Myriam E. Rodriguez, Junhwan Kim, Malcolm E. Kenney, Nancy L. Oleinick, and Vernon E. Anderson "Protein oxidation by the phthalocyanine photosensitizer Pc 4 and light: detection of a unique singlet oxygen-generated product in cytochrome c", Proc. SPIE 6845, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XVII, 684507 (11 February 2008); https://doi.org/10.1117/12.763779
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