Activation of Platinum(IV) Prodrugs by Cytochrome c and Characterization of the Protein Binding Sites
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
27505350
DOI
10.1021/acs.molpharmaceut.6b00438
PII: 10.1021/acs.molpharmaceut.6b00438
Knihovny.cz E-resources
- Keywords
- Pt(IV) complexes, anticancer prodrugs, cytochrome c, reductive activation,
- MeSH
- Cisplatin chemistry metabolism MeSH
- Cytochromes c chemistry metabolism MeSH
- Mass Spectrometry MeSH
- Magnetic Resonance Spectroscopy MeSH
- Molecular Structure MeSH
- NAD chemistry metabolism MeSH
- Platinum chemistry metabolism MeSH
- Prodrugs chemistry metabolism MeSH
- Antineoplastic Agents chemistry metabolism MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Chromatography, High Pressure Liquid MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cisplatin MeSH
- Cytochromes c MeSH
- NAD MeSH
- Platinum MeSH
- Prodrugs MeSH
- Antineoplastic Agents MeSH
Platinum(IV) complexes generally require reduction to reactive Pt(II) species to exert their chemotherapeutic activity. The process of reductive activation of (15)N-labeled (OC-6-43)-bis(acetato)diamminedichloridoplatinum(IV), in the presence of nicotinamide adenine dinucleotide (NADH) and horse heart cytochrome c (cyt c), was monitored by (1)H,(15)N-HSQC NMR spectroscopy and protein digestion experiments. It has been shown that cyt c plays a catalytic role in the transfer of two reducing equivalents from NADH to Pt(IV) species. Noncovalent interactions between reduced monoaqua cisplatin (cis-[PtCl((15)NH3)2(H2O)](+)) and the protein, in the proximity of the heme cofactor, and also covalent binding of platinum to the protein region around Met65 and Met80 take place.
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