title: Activation of Platinum(IV) Prodrugs by Cytochrome c and Characterization of the Protein Binding Sites.
abstract: 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.
authors: Department of Chemistry, University of Bari "A. Moro" , via E. Orabona, 4, 70125 Bari, Italy.
authors: Alessia
authors: A
authors: Lasorsa
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic , v.v.i, Královopolská 135, CZ-61265 Brno, Czech Republic.|Department of Biophysics, Faculty of Science, Palacky University , 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors: Olga
authors: O
authors: Stuchlíková
authors: Institute of Biophysics, Academy of Sciences of the Czech Republic , v.v.i, Královopolská 135, CZ-61265 Brno, Czech Republic.
authors: Viktor
authors: V
authors: Brabec
authors: Department of Chemistry, University of Bari "A. Moro" , via E. Orabona, 4, 70125 Bari, Italy.
authors: Giovanni
authors: G
authors: Natile
authors: Department of Chemistry, University of Bari "A. Moro" , via E. Orabona, 4, 70125 Bari, Italy.
authors: Fabio
authors: F
authors: Arnesano
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism; D045304:Cytochromes c / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D010984:Platinum / Q000737:chemistry / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D009243:NAD; D010984:Platinum; D045304:Cytochromes c; D002945:Cisplatin
keywords: Pt(IV) complexes; anticancer prodrugs; cytochrome c; reductive activation