Structural insight of DNA topoisomerases I from camptothecin-producing plants revealed by molecular dynamics simulations
| Autor: | Arthitaya Meeprasert, Thanyada Rungrotmongkol, Hiroshi Sudo, Tyuji Hoshino, Supaart Sirikantaramas, Mami Yamazaki, Kazuki Saito, Hideyoshi Fuji |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
endocrine system
endocrine system diseases Protein Conformation Plant Science Molecular Dynamics Simulation Horticulture medicine.disease_cause Biochemistry chemistry.chemical_compound Camptotheca medicine Humans heterocyclic compounds Amino Acid Sequence neoplasms Molecular Biology Genetics Mutation Molecular Structure biology Indole alkaloid Sensitive-plant Topoisomerase General Medicine biology.organism_classification Antineoplastic Agents Phytogenic Biological Evolution digestive system diseases DNA Topoisomerases Type I chemistry Drug Resistance Neoplasm biology.protein Camptothecin Topotecan Topoisomerase I Inhibitors Linker DNA medicine.drug |
| Zdroj: | Phytochemistry. 113:50-56 |
| ISSN: | 0031-9422 |
| DOI: | 10.1016/j.phytochem.2015.02.012 |
| Popis: | DNA topoisomerase I (Top1) catalyzes changes in DNA topology by cleaving and rejoining one strand of the double stranded (ds)DNA. Eukaryotic Top1s are the cellular target of the plant-derived anticancer indole alkaloid camptothecin (CPT), which reversibly stabilizes the Top1-dsDNA complex. However, CPT-producing plants, including Camptotheca acuminata , Ophiorrhiza pumila and Ophiorrhiza liukiuensis , are highly resistant to CPT because they possess point-mutated Top1. Here, the adaptive convergent evolution is reported between CPT production ability and mutations in their Top1, as a universal resistance mechanism found in all tested CPT-producing plants. This includes Nothapodytes nimmoniana , one of the major sources of CPT. To obtain a structural insight of the resistance mechanism, molecular dynamics simulations of CPT– resistant and –sensitive plant Top1s complexed with dsDNA and topotecan (a CPT derivative) were performed, these being compared to that for the CPT-sensitive human Top1. As a result, two mutations, Val617Gly and Asp710Gly, were identified in O. pumila Top1 and C. acuminata Top1, respectively. The substitutions at these two positions, surprisingly, are the same as those found in a CPT derivative-resistant human colon adenocarcinoma cell line. The results also demonstrated an increased linker flexibility of the CPT–resistant Top1, providing an additional explanation for the resistance mechanism found in CPT-producing plants. These mutations could reflect the long evolutionary adaptation of CPT-producing plant Top1s to confer a higher degree of resistance. |
| Databáze: | OpenAIRE |
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