Pyridoxal 5'-phosphate inactivates DNA topoisomerase IB by modifying the lysine general acid
| العنوان: | Pyridoxal 5'-phosphate inactivates DNA topoisomerase IB by modifying the lysine general acid |
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| المؤلفون: | Leon V. Karabashyan, Serge Christmann-Franck, Jacqueline J. Vermeersch, Serge Fermandjian, Gilles Mirambeau, P. Arsène Der Garabedian |
| المساهمون: | Biochimie des signaux régulateurs cellulaires et moléculaires (BSRCM), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Accelrys, Institute of Molecular Biology, National Academy Science of Armenia, Institut Gustave Roussy (IGR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | Nucleic Acids Research Nucleic Acids Research, Oxford University Press, 2004, 32 (18), pp.5649-57. ⟨10.1093/nar/gkh897⟩ Nucleic Acids Research, 2004, 32 (18), pp.5649-57. ⟨10.1093/nar/gkh897⟩ |
| بيانات النشر: | HAL CCSD, 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Models, Molecular, Lysine, Peptide, chemical and pharmacologic phenomena, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, immune system diseases, Genetics, Humans, MESH: Lysine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enzyme Inhibitors, Binding site, Pyridoxal phosphate, Pyridoxal, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Binding Sites, MESH: Humans, biology, MESH: Adenosine Diphosphate, Topoisomerase, MESH: DNA Topoisomerases, Type I, Eukaryotic, Active site, Articles, nervous system diseases, Adenosine Diphosphate, Enzyme, DNA Topoisomerases, Type I, chemistry, Biochemistry, MESH: Binding Sites, MESH: Enzyme Inhibitors, Pyridoxal Phosphate, 030220 oncology & carcinogenesis, biology.protein, lipids (amino acids, peptides, and proteins), MESH: Pyridoxal Phosphate, MESH: Models, Molecular |
| الوصف: | International audience; The present results demonstrate that pyridoxal, pyridoxal 5'-phosphate (PLP) and pyridoxal 5'-diphospho-5'-adenosine (PLP-AMP) inhibit Candida guilliermondii and human DNA topoisomerases I in forming an aldimine with the epsilon-amino group of an active site lysine. PLP acts as a competitive inhibitor of C.guilliermondii topoisomerase I (K(i) = 40 microM) that blocks the cleavable complex formation. Chemical reduction of PLP-treated enzyme reveals incorporation of 1 mol of PLP per mol of protein. The limited trypsic proteolysis releases a 17 residue peptide bearing a lysine-bound PLP (KPPNTVIFDFLGK*DSIR). Targeted lysine (K*) in C.guilliermondii topoisomerase I corresponds to that found in topoisomerase I of Homo sapiens (K532), Candida albicans (K468), Saccharomyces cerevisiae (K458) and Schizosaccharomyces pombe (K505). In the human enzyme, K532, belonging to the active site acts as a general acid catalyst and is therefore essential for activity. The spatial orientation of K532-PLP within the active site was approached by molecular modeling using available crystallographic data. The PLP moiety was found at close proximity of several active residues. PLP could be involved in the cellular control of topoisomerases IB. It constitutes an efficient tool to explore topoisomerase IB dynamics during catalysis and is also a lead for new drugs that trap the lysine general acid. |
| اللغة: | English |
| تدمد: | 0305-1048 1362-4962 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e29a2114da9f7369dc300ce147921422 https://hal.archives-ouvertes.fr/hal-00284752 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e29a2114da9f7369dc300ce147921422 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 03051048 13624962 |
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