title: The reaction of a platinated methionine motif of CTR1 with cysteine and histidine is dependent upon the type of precursor platinum complex.
abstract: The human copper protein (hCTR1) is believed to facilitate the cellular uptake of cisplatin. Cisplatin likely binds to the methionine (Met)-rich motifs located in the N-terminus of hCTR1, and ligand exchange would be essential if cisplatin has to pass through the hCTR1 channel. In this work, we investigated the reaction between platinated adducts of a methionine-rich motif of yeast CTR1 (Mets7) and N-acetyl-cysteine (AcCys) or N-acetyl-histidine (AcHis), mimicking metal-binding residues downstream the CTR1 channel. Platination involved two cis-compounds, cisplatin and oxaliplatin, and one monofunctional complex, cis-diammine(pyridine)chloridoplatinum(II) (cDPCP). The reactions were monitored by HPLC and the products were characterized by ESI-MS. The results indicate different reactivities depending upon the platinum complex. The cisplatin/Mets7 adduct reacts readily with both cysteine and histidine (t1/2<2min). In contrast, the oxaliplatin/Mets7 adduct reacts with cysteine but not with histidine, whereas cDPCP/Mets7 adduct reacts with histidine but not with cysteine. Hence, Mets7 adducts of these platinum complexes exhibit different reactivities towards downstream coordinating amino acids. These results suggest that each platinum complex possesses different reactivities and consequently may lead to differences in their cellular distribution and bioactivity.
authors.affiliation: CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei Anhui 230026, China.
authors.forename: Guolin
authors.initials: G
authors.lastname: Ma
authors.affiliation: CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei Anhui 230026, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wu
authors.affiliation: CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei Anhui 230026, China.
authors.forename: Xuelei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Chemistry, University of Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
authors.affiliation: Department of Chemistry, University of Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.affiliation: Department of Chemistry, University of Bergen, Norway.
authors.forename: Einar
authors.initials: E
authors.lastname: Sletten
authors.affiliation: CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei Anhui 230026, China. Electronic address: liuyz@ustc.edu.cn.
authors.forename: Yangzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D000079923:Copper Transporter 1; D003545:Cysteine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D008715:Methionine / Q000737:chemistry; D008969:Molecular Sequence Data; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D000077150:Oxaliplatin; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C490078:CTR1 protein, S cerevisiae; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D009944:Organoplatinum Compounds; D029701:Saccharomyces cerevisiae Proteins; D000077150:Oxaliplatin; D006639:Histidine; D008715:Methionine; D003545:Cysteine; D002945:Cisplatin
keywords: Anticancer drugs; Copper transport proteins; Metal coordination; Platinum complexes; Substitution reactions