The anticancer drug cisplatin can cross-link the interdomain zinc site on human albumin

Abstract

Cisplatin, cis-[Pt(Cl 2 (NH 3 ) 2 ], can crosslink residues His67 of domain I and His247 of domain II in human albumin, occupying the major binding site for the essential metal zinc on the protein.Cisplatin is a widely used anticancer agent, particularly effective for treating solid tumors such as ovarian, testicular, bladder, head and neck cancers. 1 In vivo, cisplatin is converted to its active forms by aquation, 2 being highly reactive toward biomolecules such as DNA 3 and proteins. 4 Although DNA is probably the crucial target for cisplatin inducing apoptosis and cell death, 5 it is now increasingly recognized that an understanding of its reactions with proteins is very important for understanding its metabolism and side-effects. One day after intravenous administration, 65 to 98% of cisplatin is bound to blood plasma proteins, 6 and most of the Pt (50-61%) from cisplatin added to human blood plasma at physiologically-relevant doses is bound to albumin. 7 Albumin, a 66 kDa single-chain protein consisting of 3 isostructural domains, 8 and present in blood at ca. 0.6 mM, can bind and transport a variety of endogenic and exogenic substances, such as fatty acids, bilirubin, pharmaceuticals and metal ions. 9 Despite numerous reports on the interaction of cisplatin with albumin, few Pt binding sites have been characterized unambiguously. According to NMR spectroscopic studies, 10 a Met298 S,N-macrochelate is a major cisplatin binding site, and monofunctional adducts involving Cys34 and surface histidine residues are also be formed. Recently, Cys34, Met329, Tyr150 (or Tyr148) and Asp375 (or Glu376) were identified as cisplatin binding sites using multidimensional liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), after

Hemorrhagic Shock and Surgical Stress Alter Distribution of Labile Zinc Within High- and Low-Molecular-Weight Plasma Fractions

“…Binding of the divalent cation Co 2+ in serum is impaired in ischemic and systemic inflammatory states, and is proposed for semiquantitative monitoring of modification of plasma albumin [40–43]. Since the Zn 2+ binding sites in albumin include other divalent cations such as Cd 2+ and the multivalent cation cisplatin [44, 45], it likely that the same site is modifiable by ischemic and oxidant stress in hemorrhagic shock. In conjunction with the findings of the current study, these considerations suggest that persistence of impaired Zn 2+ binding state of the HMW plasma fraction.…”

Mass Spectrometry Evidence for Cisplatin As a Protein Cross-Linking Reagent

“…also found that cisplatin cross-links domains of albumin. 27 However, whether cisplatin can function as a cross-linking reagent has not been fully explored. Platinum(II) has a strong affinity for sulfur and nitrogen containing ligands, and the coordination sites are the side chains of methionine (Met), cysteine (Cys) and histidine (His), namely, thioether, sulfhydryl, and imidazole.…”

Diversity in Gold Finger Structure Elucidated by Traveling‐Wave Ion Mobility Mass Spectrometry

“…[11] Theselected regions are shown in Figure 3. Crosslinking is destroyed upon CID fragmentation, producing adiscrete set of shorter, but still gold-bound fragments from which the original binding sites can be deduced, as observed in MS/MS studies of aplatinum-crosslinked peptide.…”