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Carbonyl reductases and pluripotent hydroxysteroid dehydrogenases of the short-chain dehydrogenase/reductase superfamily : structural aspects of oligomerization in 3-hydroxysteroid dehydrogenase/carbonyl reductase from comamonas testosteroni / Frank Hoffmann

From the introduction: Metabolic reduction is the counterpart to oxidative pathways and plays an important role in the phase-I metabolism of carbonyl group bearing substances. Carbonyl reduction means the formation of a hydroxy group from a reactive aldehyde or ketone moiety and is generally regarde... Full description

PPN (Catalogue-ID): 772307652
Personen: Hoffmann, Frank [VerfasserIn]
Format: eBook eBook
Language: English
Published: Hamburg, Diplom.de, [2009]
Series: Dissertation/Doktorarbeit
Hochschule: Dissertation, Philipps-Universität Marburg, 2009
Subjects:

Hydroxysteroid-Dehydrogenasen / Carbonyl-Reductase / Molekulardynamik / Modellierung

Formangabe: Hochschulschrift
Physical Description: 1 Online-Ressource (211 Seiten), Illustrationen.
ISBN: 3-8366-3391-4
978-3-8366-3391-8

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245 1 0 |a Carbonyl reductases and pluripotent hydroxysteroid dehydrogenases of the short-chain dehydrogenase/reductase superfamily  |b structural aspects of oligomerization in 3-hydroxysteroid dehydrogenase/carbonyl reductase from comamonas testosteroni  |c Frank Hoffmann 
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520 |a From the introduction: Metabolic reduction is the counterpart to oxidative pathways and plays an important role in the phase-I metabolism of carbonyl group bearing substances. Carbonyl reduction means the formation of a hydroxy group from a reactive aldehyde or ketone moiety and is generally regarded as an inactivation or detoxification step since the resulting alcohol is easier to conjugate and to eliminate. Not only are these carbonyl-containing compounds widespread in the environment and enter the body as xenobiotics and environmental pollutants, but they can also be generated endogenously through normal catabolic oxidation and deamination reactions. Many endogenous compounds such as biogenic amines, steroids, prostaglandins and other hormones are metabolized through carbonyl intermediates. In addition, lipid peroxidation within the cell results in the production of reactive carbonyls such as acrolein, 4-hydroxynonenal, 4-oxononenal and malon-dialdehyde, while oxidative damage to DNA generates base propenals. Dietary sources of carbonyl-containing compounds are diverse and include aldehydes found in fruits as well as the breakdown product of ethanol, acetaldehyde. Pharmacologic drugs represent further sources of exposure to carbonyl-containing compounds. From the pharmacologist’s point of view, carbonyl reduction has been shown to be of significance in various inactivation processes of drugs bearing a carbonyl group. On the other hand, the carbinols formed may retain therapeutic potency, thus prolonging the pharmacodynamic effect of the parent drug, or, in some instances, a compound gains activity through carbonyl reduction. From the toxicologist’s point of view, carbonyl reduction plays an important role in the toxification of drugs such as daunorubicin and doxorubicin (cf. chapter 4), whereas numerous reports corroborate the concept of carbonyl-reducing enzymes being involved in detoxification processes of endogenous and xenobiotic reactive carbonyl compounds. Compared with the oxidative cytochrome P450 (CYP) system, carbonyl-reducing enzymes had, for a long time, received considerably less attention. However, the advancement of carbonyl reductase molecular biology has allowed the identification and characterization of several carbonyl-reducing enzymes, including pluripotent hydroxysteroid dehydrogenases that are involved in xenobiotic carbonyl compound metabolism, in addition to catalyzing the oxidoreduction of their physiologic steroid substrates.Inhaltsverzeichnis:Table of Contents: Abstract5 IIntroduction6 I.1Carbonyl Reduction6 I.2Enzymes Mediating Carbonyl Reduction7 1.1The Aldo-Keto Reductase (AKR) Superfamily9 1.2Short-Chain Dehydrogenase/Reductase (SDR) Superfamily10 I.3Hydroxysteroid Dehydrogenases as Carbonyl Reductases11 IIGeneral Features of the SDR Superfamily Enzymes13 II.1Historical Background: Functional Characterization13 II.2SDR Superfamily Classification14 II.3Structural Features of the SDR Members16 II.3.1Catalytic Triade and Catalytic Mechanism18 II.3.2Substrate Binding and Substrate-Binding Loop21 II.3.3Cofactor Binding22 II.3.4C-terminal Extension and 310-Helices23 II.3.5Oligomerization and Interfaces23 IIIPluripotent Carbonyl Reductases of the SDR Superfamily27 III.1Carbonyl Reductases in Non-Mammals29 III.1.13(/20ß-Hydroxysteroid Dehydrogenase of Streptomyces hydrogenans29 III.1.23(-Hydroxysteroid Dehydrogenase/Carbonyl Reductase of Comamonas testosteroni30 III.1.3Insect Carbonyl Reductase: Sniffer of Drosophila melanogaster31 III.2Carbonyl Reductases in Mammals33 III.2.1Monomeric Cytosolic NADPH-Dependent Carbonyl Reductases33 III.2.1.1Human Carbonyl Reductase 1 (CBR1)33 III.2.1.29-Keto-Prostaglandin Reductase and 15-Hydroxy-Prostaglandin Dehydrogenase36 III.2.1.3Human Carbonyl Reductase 3 (CBR3) and 4 (CBR4)37 III.2.1.4Chinese Hamster Carbonyl Reductases (CHCR 1-3)38 III.2.1.5Rat Carbonyl Reductases (iCR, nCR, rtCR)39 III.2.1.6Pig Testicular Carbonyl Reductase (PTCR)40 III.2.1.7Tetrameric Peroxisomal Carbonyl Reductase41 III.2.1.8Tetrameric Mitochondrial Carbonyl Reductases42 III.2.1.9Dimeric Microsomal Carbonyl Reductase: 11(-HSD Type 143 IVBiological Functions of Carbonyl-Reducing Enzymes48 IV.1Roles in Steroid and Prostaglandin Metabolism48 IV.2Tetrahydrobiopterin Synthesis49 IV.3Neuroprotection by Carbonyl Reductase?51 IV.4Quinone Detoxification54 IV.5Carbonyl Reduction in Drug Metabolism and Pharmacology56 IV.6Role in Chemotherapy Resistance58 IV.7Protection against Tobacco Smoke-Derived Lung Cancer61 IV.8Detoxification of Insecticides65 VPhysiological Implications66 VIPerspectives67 Zusammenfassung68 VIReferences92 VIIFigure/Table List:92Textprobe:Text Sample: Chapter III.8, Detection of Overexpressed Proteins: In order to control the purity of the enzyme preparations or to perform Western blot analysis, polyacrylamide gel electrophoresis under denaturing conditions was performed to separate proteins according to their molecular weights. According to their different amino acid (aa) composition proteins carry different electric charges. SDS incorporates in constant rates into the proteins masking their individual charge from their aa-composition. After SDS-treatment the proteins differ only in their molecular mass and move in the constant electric field towards the anode. Preparation of the gel: The electrophoresis was employed using the BioRad electrophoresis apparatus Mini Protean II cell (BioRad, München, Germany). The gels (80 mm × 65 mm × 0,75 mm) composition is indicated in ‘materials’. Cleaning of the glass plates was performed using 70% ethanol. Assembling of the electrophoreses apparatus was carried out according to the manufacturers instructions. For the vertical gel electrophoresis first the resolving gel was prepared. Polymerization of the solution is started by APS and TEMED which therefore should be added immediate before the solution is filled between the glass plates. After polymerization the stacking gel was prepared and filled in. In a final step the comb is placed in the glass plates. To obtain a resolving of proteins between 20 and 70 kDa a 10% acrylamide/bisacrylamide gel was prepared. Electrophoresis: Before electrophoresis the protein samples were diluted 1:2 with protein loading buffer and denatured for 5 min at 95oC. Subsequently, 3-20 µl of the samples were loaded to the gel. The electrophoresis chamber was completely filled with Tris/glycine-electrophoresis buffer. The electrophoresis was started with a voltage of 80 V until the bromphenol blue marker reached the top of the separating gel then performed at 150 V until the tracking dye reached the bottom of the separating gel. As molecular weights standards in SDS-PAGE different Molecular Weight Astandards have been used. After electrophoresis, the proteins were visualized by staining the gel at room temperature for several hours in a solution of Coomassie Brillant blue R 250. Destaining was carried out at room temperature in a mixture of water/isopropanol/acetic acid (81:12:7). Determination of Protein Concentrations: Protein concentrations were determined with the BioRad Protein Microassay, a dye-binding assay based on the differential colour change of a dye in response to various concentrations of protein (Bradford, 1976). The principle of this method is based on the observation that the absorbance maximum for an acidic solution of Coomassie Brillant Blue G-250 shifts from 465 nm to 595 nm when binding to protein occurs. Each time the assay was performed, a standard curve was prepared using bovine serum albumin as protein standard (0-10 mg ml-1); A595 was corrected for the blank. 0.8 ml of appropriately diluted samples or bovine serum albumin were mixed with 0.2 ml dye protein reagent and the absorbance of the solution at 595 nm was measured at room temperature with a spectrophotometer (Kontron) after 10 minutes. Protein Immunodetection by Western blot Analysis: After electrophoresis, the protein samples were transferred from an unstained SDS-polyacrylamide gel to polyvinylidene fluoride membrane (ProBlott PVDF-Membran, Applied Biosystems, Weiterstadt, Germany) using a Semy-dry transfer system (Trans-Blot S... 
520 |a Inhaltsangabe:Introduction: Metabolic reduction is the counterpart to oxidative pathways and plays an important role in the phase-I metabolism of carbonyl group bearing substances. Carbonyl reduction means the formation of a hydroxy group from a reactive aldehyde or ketone moiety and is generally regarded as an inactivation or detoxification step since the resulting alcohol is easier to conjugate and to eliminate. Not only are these carbonyl-containing compounds widespread in the environment and enter the body as xenobiotics and environmental pollutants, but they can also be generated endogenously through normal catabolic oxidation and deamination reactions. Many endogenous compounds such as biogenic amines, steroids, prostaglandins and other hormones are metabolized through carbonyl intermediates. In addition, lipid peroxidation within the cell results in the production of reactive carbonyls such as acrolein, 4-hydroxynonenal, 4-oxononenal and malon-dialdehyde, while oxidative damage to DNA generates base propenals. Dietary sources of carbonyl-containing compounds are diverse and include aldehydes found in fruits as well as the breakdown product of ethanol, acetaldehyde. Pharmacologic drugs represent further sources of exposure to carbonyl-containing compounds. From the pharmacologist’s point of view, carbonyl reduction has been shown to be of significance in various inactivation processes of drugs bearing a carbonyl group. On the other hand, the carbinols formed may retain therapeutic potency, thus prolonging the pharmacodynamic effect of the parent drug, or, in some instances, a compound gains activity through carbonyl reduction. From the toxicologist’s point of view, carbonyl reduction plays an important role in the toxification of drugs such as daunorubicin and doxorubicin (cf. chapter 4), whereas numerous reports corroborate the concept of carbonyl-reducing enzymes being involved in detoxification processes of endogenous and xenobiotic reactive carbonyl compounds. Compared with the oxidative cytochrome P450 (CYP) system, carbonyl-reducing enzymes had, for a long time, received considerably less attention. However, the advancement of carbonyl reductase molecular biology has allowed the identification and characterization of several carbonyl-reducing enzymes, including pluripotent hydroxysteroid dehydrogenases that are involved in xenobiotic carbonyl compound metabolism, in addition to catalyzing the oxidoreduction of their physiologic [... 
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