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51.
Sfondouris J Rajagopalan L Pereira FA Brownell WE 《The Journal of biological chemistry》2008,283(33):22473-22481
The lateral membrane of the cochlear outer hair cell (OHC) is the site of a membrane-based motor that powers OHC electromotility, enabling amplification and fine-tuning of auditory signals. The OHC membrane protein prestin plays a central role in this process. We have previously shown that membrane cholesterol modulates the peak voltage of prestin-associated nonlinear capacitance in vivo and in vitro. The present study explores the effects of membrane cholesterol and docosahexaenoic acid content on the peak and magnitude of prestin-associated charge movement in a human embryonic kidney (HEK 293) cell model. Increasing membrane cholesterol results in a hyperpolarizing shift in the peak voltage of the nonlinear capacitance (Vpkc) and a decrease in the total charge movement. Both measures depend linearly on membrane cholesterol concentration. Incubation of cholesterol-loaded cells in cholesterol-free media partially restores the Vpkc toward normal values but does not have a compensatory effect on the total charge movement. Decreasing membrane cholesterol results in a depolarizing shift in Vpkc that is restored toward normal values upon incubation in cholesterol-free media. However, cholesterol depletion does not alter the magnitude of charge movement. In contrast, increasing membrane docosahexaenoic acid results in a hyperpolarizing shift in Vpkc that is accompanied by an increase in total charge movement. Our results quantify the relation between membrane cholesterol concentration and prestin-associated charge movement and enhance our understanding of how membrane composition modulates prestin function. 相似文献
52.
James J Truglio Karsten Theis Silke Leimkühler Roberto Rappa K V Rajagopalan Caroline Kisker 《Structure (London, England : 1993)》2002,10(1):115-125
Xanthine dehydrogenase (XDH), a complex molybdo/iron-sulfur/flavoprotein, catalyzes the oxidation of hypoxanthine to xanthine followed by oxidation of xanthine to uric acid with concomitant reduction of NAD+. The 2.7 A resolution structure of Rhodobacter capsulatus XDH reveals that the bacterial and bovine XDH have highly similar folds despite differences in subunit composition. The NAD+ binding pocket of the bacterial XDH resembles that of the dehydrogenase form of the bovine enzyme rather than that of the oxidase form, which reduces O(2) instead of NAD+. The drug allopurinol is used to treat XDH-catalyzed uric acid build-up occurring in gout or during cancer chemotherapy. As a hypoxanthine analog, it is oxidized to alloxanthine, which cannot be further oxidized but acts as a tight binding inhibitor of XDH. The 3.0 A resolution structure of the XDH-alloxanthine complex shows direct coordination of alloxanthine to the molybdenum via a nitrogen atom. These results provide a starting point for the rational design of new XDH inhibitors. 相似文献
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54.
Hubert Josien Thomas Bara Murali Rajagopalan John W. Clader William J. Greenlee Leonard Favreau Lynn A. Hyde Amin A. Nomeir Eric M. Parker Lixin Song Lili Zhang Qi Zhang 《Bioorganic & medicinal chemistry letters》2009,19(21):6032-6037
A new class of 2,6-disubstituted morpholine N-arylsulfonamide γ-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Aβ levels in Tg CRND8 mice upon oral administration were identified. 相似文献
55.
Rat liver xanthine dehydrogenase, type D, has been isolated directly from crude extracts as an antibody complex and its properties compared with those of two oxidase forms of the enzyme, heat-treated type O and trypsin-treated type O, also isolated as antibody complexes. The type D antibody complex displays electron acceptor specificities and electron paramagnetic resonance properties characteristic of an NAD+-dependent dehydrogenase whereas the trypsin-treated type O complex behaves as an O2-utilizing oxidase. The heat-treated type O complex displays intermediate behavior. After electrophoresis in dodecyl sulfate-urea-acrylamide gels, type D and heated type O enzymes show single polypeptide bands, each of approximately 150,000 molecular weight. The trypsinized type O also shows one major band but with an approximate molecular weight of 130,000. Purified type D enzyme, when proteolytically treated, is converted to an oxidase with increased mobility on polyacrylamide gels. The 150,000 molecular weight subunit is cleaved into smaller subunits during proteolysis. Treatment with 5,5′-dithiobis-(2-nitrobenzoic acid) converts the type D enzyme, whether isolated as the purified enzyme or as the immune precipitate, to type O enzyme in a time-dependent manner. Titration of type D and the two type O antibody complexes with 5,5′-dithiobis-(2-nitrobenzoic acid) reveals that type D and heated type O each has approximately 28 reactive sulfhydryls, whereas the trypsinized type O has only 8 such groups. Many of the free sulfhydryls are vicinal and form disulfide bonds during the conversion to an oxidase by this reagent. Unproteolyzed preparations of type O rat liver enzyme and milk xanthine oxidase are converted to type D enzymes by treatment with dithiothreitol. The converted enzymes display electron acceptor specificities and epr properties characteristic of an NAD+-dependent dehydrogenase molecule. 相似文献
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57.
The CO----methylene blue and CO----dichlorophenol indophenol activities of carbon monoxide oxidase were specifically activated upon aerobic incubation with selenite, whereas the NADH----methylene blue activity was not altered. Fully active enzyme contained selenium, molybdenum, and flavin adenine dinucleotide in a 1:1:1 ratio. Selenium was covalently bound to the protein, probably between the sulfurs of half-cystine residues, and not a constituent of the molybdenum cofactor. The action of selenite was directed to the cytoplasmic species of carbon monoxide oxidase exclusively, whereas the CO----methylene blue activity of the membrane-bound enzyme remained unaffected. 相似文献
58.
Swaran J. S. Flora Shashi N. Dube Rajagopalan Vijayaraghavan Satish C. Pant 《Biological trace element research》1997,58(3):197-208
Gallium arsenide (GaAs), a group III-VA intermetallic semiconductor, possesses superior electronic and optical properties and has a wide application in electronic industry. Exposure to GaAs in the semiconductor industries could be a possible occupational risk. The aim of the present study was to determine the dose-dependent effect of single oral exposure to GaAs (500, 1000, or 2000 mg/kg) on some biochemical variables in heme synthesis pathway and few selected physiological variables at d 1, 7, and 15 following administration. The results indicate that GaAs produced a significant effect on the activity of δ-aminolevulinic acid dehydratase (ALAD) in blood and heart (particularly at d 7) following exposure to 2000 mg/kg, whereas urinary δ-aminolevulinic acid (ALA) excretion was elevated only at d 7. No marked influence of GaAs on blood hemoglobin, zinc protoporphyrin, and packed cell volume was noticed. Blood glutathione (GSH) was significantly reduced at d 7, but remained unchanged at two other time intervals. On the other hand, heart GSH contents remained uninfluenced on GaAs exposure. Most of the physiological variables, viz. blood pressure, heart and respiration rate, and twitch response, remained unchanged, except for some minor alterations observed at d 7 and 15 following exposure to GaAs at a dose of 2000 mg/kg. Blood gallium concentration was not detectable in normal animals and rats exposed to 500 mg/kg GaAs. Blood arsenic concentration was, however, detectable even at the a lower dose level and increased in a dose-dependent manner. All these changes showed a recovery pattern at d 21, indicating that the alterations are reversible. 相似文献
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60.
The importance of intramolecular disulfides in a noncovalent dimeric protein interleukin-8 (IL-8) has been studied by replacing cysteines in each of the two disulfide pairs with alpha-aminobutyric acid (CH(2)-SH --> CH(2)-CH(3)). Both disulfide mutants are less stable and exist as molten globules in the monomeric state. Interestingly, both mutants dimerize, though with slightly lower affinities compared to the native protein. NMR studies suggest a molten globule-like structure also in the dimeric state. Structures, sequence analysis, and mutagenesis studies have shown that the conserved hydrophobic residues are packed against each other in the protein core and that H bonding and van der Waals interactions stabilize the dimer interface. Deleting either disulfide in IL-8 results in substantial loss in receptor activity, indicating that both disulfides are critical for function in the folded protein. These data together suggest that the packing interactions of the hydrophobic core determine IL-8 monomer fold, that disulfides play only a marginal role in dimer formation, and that the stability imparted by the disulfides is intimately coupled to fold and function. 相似文献