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Heme-protein interactions in cytochromes P450
Majerová, Kristýna ; Hudeček, Jiří (advisor) ; Stiborová, Marie (referee)
Cytochromes P450 (CYP) are monooxygenases participating reactions of the PhaseI in xenobiotic biotransformations. Better and more detailed knowledge of heme - protein interaction is crucial for understanding of function of these enzymes; in particular, of their regulation. We analyzed orientations of both heme vinyl side-chains in all X-ray structures of CYP enzymes available in the PDB data bank. For two mammalian forms, CYP 2A4 and 3A4, a more detailed analysis of the heme contacts with the apoprotein was performed, based on identification of the amino acid side chains in the vicinity. In addition to spatial information, dissociation constants and Coulombic interaction of polar residues in proximity to the heme were calculated using the PropKA web server. Deviations of the heme from planarity in both forms of P450 was investigated using the normal coordinate analysis (NSD server). Distribution of torsion angles of vinyls in position 2 and 4 of the heme shows that the side- chain at position 2 is conformationally more restricted in most P450 forms studied. Comparison of all forms shows that the range of ättainable values of torsional angles is very wide, practically unrestricted, and that the actual conformations of the heme moiety are probably determined more by the interaction with the protein,...
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Combination of ellipticine chemotherapy and a5b1 integrin-targeted therapy in human glioblastoma
Martínková, Eva ; Stiborová, Marie (advisor) ; Souček, Pavel (referee) ; Eckschlager, Tomáš (referee) ; Barberi-Heyob, Muriel (referee)
Charles University Prague Faculty of Science Department of Biochemistry SUMMARY OF THE THESIS COMBINATION OF ELLIPTICINE CHEMOTHERAPY AND α5β1 INTEGRIN-TARGETED THERAPY IN HUMAN GLIOBLASTOMA by MARTÍNKOVÁ Eva Supervisors: Prof. RNDr. Marie STIBOROVÁ, DrSc. Dr. Monique DONTENWILL 2 Table
of
Contents INTRODUCTION............................................................................................................................... 3
AIMS
OF
THE
STUDY ...................................................................................................................... 5
RESULTS............................................................................................................................................. 6
PART
A ................................................................................................................................................................6
PART
B.................................................................................................................................................................6
DISCUSSION....................................................................................................................................... 8
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Study on potentiaion of pharmacological efficiencies of ellipticine
Vranová, Iveta ; Mrázová, Barbora (referee) ; Stiborová, Marie (advisor)
Cytotoxic chemotherapy offers tool for clinical treatment of neoplasia. One of the drugs suitable for chemotherapy is ellipticine. Ellipticine is an alkaloid, which has significant antineoplastic properties. It acts as a DNA intercalator, inhibitor of topoisomerase II and forms also covalent DNA adducts mediated by cytochrome P450 and/or peroxidases. Oxidation of ellipticine by CYP (CYP3A4, CYP1A1/2, CYP2C9, CYP1B1) provides several metabolites (7-hydroxyellipticine, 9-hydroxyellipticine, 12-hydroxyellipticine, 13- hydroxyellipticine, and ellipticine N2 -oxide). Metabolites 12-hydroxyellipticine and 13- hydroxyellipticine, formed by CYP3A4, are responsible for formation of two major DNA adducts. Two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium were proposed as a reactive species binding to DNA. The main metabolites generated by peroxidases are the ellipticine dimer and ellipticine N2 -oxide, which provide the same carbenium ions and same DNA adducts. Modern chemotherapy uses targeting for higher selectivity for malignant cells and lower cytotoxicity for normal cells. Ellipticine-conjugates and his derivates (N-(2-hydroxypropyl)methakrylamid-ellipticine conjugates, vasoactive intestinal peptide-ellipticine conjugates and human serum albumin-ellipticine conjugates) and epidermal...
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Nephropathy and tumour development caused by plant alkaloids aristolochic acid
Bárta, František ; Šácha, Pavel (referee) ; Stiborová, Marie (advisor)
Aristolochic acids (AA) are alkaloids contained in plant species of the family Aristolochiaceae. These plants are used since antiquity in traditional medicine to treatment of many varied diseases. There are known anti-inflammatory effects of these compounds, however these alkaloids exhibit mutagenic and carcinogenic properties. Despite of this fact, plant extracts AA are still used in traditional medicine, e.g. in China, India, Taiwan. Aristolochic acids are proven to be the cause of disease designated Aristolochic Acid Nephropathy (AAN, theretofore known as Chinese Herbs Nephropathy (CHN). This unusual nephropathy leads to a total renal failure. The late complication of this disease is the development of tumours in urothelial tissue of patients. AA can form persistent stable covalent DNA adducts. Formation of these DNA adducts lead to AT→TA transversion, the unique mutation in tumour suppressor gene p53 responsible for tumour formation. Balkan Endemic Nephropathy (BEN) is associated with AA, too. In this instance is supported also influence of another factors, e.g. mycotoxins (ochratoxin A). However, in all probability AA contribute to a development of this disease particularly. This hypothesis is supported by finding of AA-DNA adducts in tissues of patients suffering from AAN and BEN and that of...
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