Covalent binding of cisplatin impairs the function of Na+/K+-ATPase by binding to its cytoplasmic part
| Autor: | Miroslav Huličiak, Martin Kubala, Joanna Znaleziona, Jan Vacek, Marika Havlikova, Marek Šebela, Eva Orolinová |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Protein Conformation Swine ATPase Antineoplastic Agents Cytoplasmic part Biochemistry Dephosphorylation medicine Animals Na+/K+-ATPase Cerebral Cortex Pharmacology Cisplatin biology Chemistry Transmembrane domain Catalytic cycle Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization biology.protein Phosphorylation Sodium-Potassium-Exchanging ATPase Protein Binding medicine.drug |
| Zdroj: | Biochemical Pharmacology. 83:1507-1513 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2012.02.015 |
| Popis: | This study was aimed at verifying the hypothesis that acute kidney failure accompanying cisplatin administration in the cancer therapy could be due to cisplatin interaction with the cytoplasmic part of Na + /K + -ATPase. Our results demonstrated that cisplatin-binding caused inhibition of Na + /K + -ATPase, in contrast to other platinated chemotherapeutics such as carboplatin and oxaliplatin, which are known to be much less nephrotoxic. To acquire more detailed structural information, we performed a series of experiments with the isolated large cytoplasmic segment connecting transmembrane helices 4 and 5 (C45 loop) of Na + /K + -ATPase. Electrochemistry showed that cisplatin is bound to the cysteine residues of the C45 loop, mass spectrometry revealed a modification of the C45 peptide fragment GSHMASLEAVETLGSTSTICSDK, which contains the conserved phosphorylated residue Asp369. Hence, we hypothesize that binding of cisplatin to Cys367 can cause sterical obstruction during the phosphorylation or dephosphorylation step of the Na + /K + -ATPase catalytic cycle. |
| Databáze: | OpenAIRE |
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