Interactions of cisplatin and transplatin with proteins. Comparison of binding kinetics, binding sites and reactivity of the Pt-protein adducts of cisplatin and transplatin towards biological nucleophiles.
In this manuscript we report on the interactions of cis-DDP (cisplatin, cis-diamminedichloroplatinum(II)) and trans-DDP (transplatin, trans-diamminedichloroplatinum(II)) with two model proteins, ubiquitin (Ub) and horse heart myoglobin (Mb), and attempt to answer the question whether proteins that have methionine-Pt adducts can transfer the platinum to biological nucleophiles and particularly to DNA. Our study shows that cisplatin and transplatin form different adducts with ubiquitin: transplatin forms one major adduct, trans-[Pt(Ub)(NH(3))(2)Cl], while cisplatin forms four distinct adducts, [Pt(Ub)(NH(3))(2)Cl], [Pt(Ub)(NH(3))(2)(H(2)O)], [Pt(Ub)(NH(3))(2)], and [Pt(Ub)(NH(3))]. When binding ubiquitin, Met1 is the preferred binding site of cisplatin, but not of transplatin. Cisplatin binds faster than transplatin to both ubiquitin and horse heart myoglobin. Both cisplatin and transplatin adducts form stable ternary adducts when reacted with 5'-guanosine monophosphate (5'-GMP) or a tetranucleotide. No transfer of the Pt moiety from the proteins to the nucleotides was observed. Glutathione efficiently removes the platinum from preformed adducts of both cisplatin and transplatin with ubiquitin.
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, PO Box 12065, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Tal
T
Peleg-Shulman
Yousef
Y
Najajreh
Dan
D
Gibson
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D002945:Cisplatin / Q000737:chemistry* / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000737:chemistry / Q000378:metabolism; D006736:Horses; D015394:Molecular Structure; D009206:Myocardium / Q000737:chemistry; D009211:Myoglobin / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D009211:Myoglobin; D025801:Ubiquitin; C034697:transplatin; D006157:Guanosine Monophosphate; D005978:Glutathione; D002945:Cisplatin