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Circadian clock and detoxication processes in the liver
Ludvíková, Tereza ; Pačesová, Dominika (advisor) ; Kolář, David (referee)
The circadian system influences almost all physiological processes in the mammalian body. Among other things, detoxication processes in the liver are under circadian control. Both central and peripheral clock in the liver regulate the expression of genes involved in the detoxication of xenobiotic substances and drugs. The first part of this thesis summarizes the main characteristics of the central and peripheral circadian clocks, including their molecular basis. The second part focuses on the main functions of liver tissue with a focus on detoxification processes. The emphasis of the third section is on circadian rhythms in the expression and activity of enzymes called cytochromes P450, which are the most important system catalyzing phase I detoxication, and also briefly discusses the influence of the circadian system on the expression of nuclear receptors and PAR bZIP transcription factors involved in the regulation of cytochrome P450 transcription. The last section describes the influence of the circadian system on the efficacy and toxicity of selected drugs, on paracetamol metabolism with the main purpose of describing how paracetamol-induced hepatotoxicity is affected by time of administration. Key words: circadian system, liver, detoxication, cytochrome, paracetamol
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Mechanism of tumor development and its influencing by ellipticine
Parisová, Martina ; Stiborová, Marie (advisor) ; Moserová, Michaela (referee)
Ellipticine (5.11-dimethyl-6H-pyridate [4,3-b] carbazole) is a powerful anti-cancer agent, exhibiting multiple mechanisms of action. This work describes the causes of cancer processes and summarizes the main pharmacological mechanisms and cytotoxic effects of ellipticine together with the results found in our laboratory indicating, a new mechanism of ellipticine action. Cytotoxic and mutagenic activity of ellipticine is attributed to its two mechanisms of activity ellipticine intercalation into DNA and its effectivity to inhibit topoisomerase II. Ellipticine also forms covalent DNA adducts after its oxidation with cytochromes P450 and peroxidases. Cytochromes P450 oxidize ellipticine up to five metabolites, of which 13- hydroxyellipticin, 12-hydroxyellipticin and N(2)-oxide of ellipticine are responsible for formation of two major DNA adducts. In the case of peroxidases, ellipticine is oxidized to a radical producing the ellipticine dimer and a minor ellipticine metabolite, the N(2)-oxide of ellipticine. Because of the high efficiency of ellipticine and its derivatives against various types of cancer, this coumpound is studied in detail. Its utilization for drug tangeting is a challenge for further study.
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Diversity and functions of soluble electron transporting proteins
Alexová, Eliška ; Hrdý, Ivan (advisor) ; Mach, Jan (referee)
Electron transporting proteins serve to transfer electrons between various soluble and membrane bounded enzymes and proteins in biological processes as for example respiration, photosynthesis and different kinds of energy metabolism. Electron transporting proteins occur in every living organism. The active site of electron transporting proteins contains metal ions as iron and copper, thiol or flavin group. It uses this active site for electron transfer. The redox potential is connected with electron transfer because that is a relative tendency of molecule pairs and they are able to accept or donnate electrons. When the molecules have got more negative value of redox potential, then they have got better ability to donnate electrons. Ferredoxins with iron-sulfur cluster and cytochromes with heme group have got the lowest redox potential of electron transporting proteins. On the contrary cupredoxins with copper center have got the highest redox potential. Key words: cytochrome, flavodoxin, cupredoxin, ferredoxin, thioredoxin, glutaredoxin, rubredoxin
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Mechanism of tumor development and its influencing by ellipticine
Parisová, Martina ; Stiborová, Marie (advisor) ; Moserová, Michaela (referee)
Ellipticine (5.11-dimethyl-6H-pyridate [4,3-b] carbazole) is a powerful anti-cancer agent, exhibiting multiple mechanisms of action. This work describes the causes of cancer processes and summarizes the main pharmacological mechanisms and cytotoxic effects of ellipticine together with the results found in our laboratory indicating, a new mechanism of ellipticine action. Cytotoxic and mutagenic activity of ellipticine is attributed to its two mechanisms of activity ellipticine intercalation into DNA and its effectivity to inhibit topoisomerase II. Ellipticine also forms covalent DNA adducts after its oxidation with cytochromes P450 and peroxidases. Cytochromes P450 oxidize ellipticine up to five metabolites, of which 13- hydroxyellipticin, 12-hydroxyellipticin and N(2)-oxide of ellipticine are responsible for formation of two major DNA adducts. In the case of peroxidases, ellipticine is oxidized to a radical producing the ellipticine dimer and a minor ellipticine metabolite, the N(2)-oxide of ellipticine. Because of the high efficiency of ellipticine and its derivatives against various types of cancer, this coumpound is studied in detail. Its utilization for drug tangeting is a challenge for further study.
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Nové alternativní krystalizační techniky používané pro zlepšení morfologie a difrakční kvality proteinových krystalů
TOMČOVÁ, Ivana
X-ray crystallography is used as a powerful tool to understand how a particular biomacromolecule accomplishes its various functions. In the present study, detailed atomic structure of bacterial di-heme cytochrome c4 isolated for the first time from an anaerobic organism and structure of two crystal forms of sweet protein thaumatin from the African shrub, are presented, as well as an example of how this structural knowledge of cytochrome c4 in combination with biochemical data have been used to classified the protein function. In parallel to modern high-throughput approaches in the crystallization of protein, basic research on their physico-chemical properties and molecular interactions has increasingly gained on importance in recent years. Our aim was to improve the success of any crystallization attempts significantly as well as to find alternative methods of predicting it. In this thesis two novel approaches in macromolecular crystallization are discussed. The first; newly discovered cross-crystallization method alias cross-influence procedure (CIP) with its subsequent application presented on two selected proteins. And the novelty in our second approach is the use of precise temperature-control to drive the crystallization process by keeping system in metastable zone. The understanding that the solubility and phase behavior of proteins is an essential part of the crystallization process, allows us to perform the temperature-controlled experiment (TCE), where the manipulation of the thermodynamics as well as the kinetics of the crystallization process were controlled. In order to improve crystal quality and/or morphology, the both CIP and TCE were found as useful tools in protein crystallization presented by means of crystallization of three different proteins (bacterial cyrochrome c4, glycoside hydrolase family 11 enzyme xylanase and sweet protein thaumatin). Finally, the preliminary crystallization information about three other enzymes (two haloalkane dehalogenase and one membrane protein hydrogenase) are given at the end, as a starting experiment for further X-ray diffraction analysis.
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