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1.
Joe Murphy Roger Rowlett Susan B. Smith James Hoeferlin 《Archives of biochemistry and biophysics》1980,202(2):405-413
The KI values for inhibition of thermolysin activity by N-β-phenylpropionyl-aliphatic amino acids (Gly, Ala, Val, Leu, Ile) are correlated by π, the hydrophobic substituent parameter for the amino acid side chain (log KI = ?0.73π ?1.80, correlation coefficient = 0.990). By contrast, the KI values for the corresponding benzyloxycarbonyl amino acids are poorly correlated by π, but show a good correlation with the steric parameter Es(log KI = 0.880Es ? 3.086, correlation coefficient = 0.985). Binding of β-phenylpropionyl-l-alanine is associated with an acidic residue of pK 7.3 and a basic residue of pK 8.0 in the E · I complex, and appears to raise the pK of Glu-143 by 2 units. Binding of benzyloxycarbonyl-Ala and -Phe is associated with an acidic residue of pK 8.0 and two basic residues, both with pK 8.3. Three similar pK values are observed with benzyloxycarbonyl-Phe. These results are interpreted in terms of different modes of binding of β-phenylpropionyl and benzyloxycarbonyl inhibitors. 相似文献
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Ojas A. Namjoshi Zhi-jian Wang Sundari K. Rallapalli Edward Merle Johnson Yun-Teng Johnson Hanna Ng Joachim Ramerstorfer Zdravko Varagic Werner Sieghart Samarpan Majumder Bryan L. Roth James K. Rowlett James M. Cook 《Bioorganic & medicinal chemistry》2013,21(1):93-101
Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABAA) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both α2β(2/3)γ2 (α2BzR) and α3BzR (and/or α2/α3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100 mg/kg and was devoid of sedative properties. 相似文献
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Rowlett RS Tu C McKay MM Preiss JR Loomis RJ Hicks KA Marchione RJ Strong JA Donovan GS Chamberlin JE 《Archives of biochemistry and biophysics》2002,404(2):197-209
We have cloned and overexpressed a truncated, recombinant form of beta-carbonic anhydrase from Arabidopsis thaliana. The wild-type enzyme and two site-directed variants, H216N and Y212F, have been kinetically characterized both at steady state by stopped-flow spectrophotometry and at chemical equilibrium by (18)O isotope exchange methods. The wild-type enzyme has a maximal k(cat) for CO2 hydration of 320 ms(-1) and is rate limited by proton transfer involving two residues with apparent pK(a) values of 6.0 and 8.7. The mutant enzyme H216N has a maximal k(cat) at high pH that is 43% that of wild type, but is only 5% that of wild type at pH 7.0. (18)O exchange studies reveal that the effect of the mutations H216N or Y212F is primarily on proton transfer steps in the catalytic mechanism and not in the rate of CO2-HCO3- exchange. These results suggest that residues His-216 and Tyr-212 are both important for efficient proton transfer in A. thaliana carbonic anhydrase. 相似文献
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Rowlett RM Chrestensen CA Nyce M Harp MG Pelo JW Cominelli F Ernst PB Pizarro TT Sturgill TW Worthington MT 《American journal of physiology. Gastrointestinal and liver physiology》2008,294(2):G452-G459
The MNK kinases are downstream of both the p38 and ERK MAP kinase pathways and act to increase gene expression. MNK inhibition using the compound CGP57380 has recently been reported to inhibit tumor necrosis factor (TNF) production in macrophage cell lines stimulated with Escherichia coli lipopolysaccharide (LPS). However, the range of receptors that signal through the MNK kinases and the extent of the resultant cytokine response are not known. We found that TNF production was inhibited in RAW264.7 macrophage cells by CGP57380 in a dose-responsive manner with agonists for Toll-like receptor (TLR) 2 (HKLM), TLR4 (Salmonella LPS), TLR6/2 (FSL), TLR7 (imiquimod), and TLR9 (CpG DNA). CGP57380 also inhibited the peak of TNF mRNA production and increased the rate of TNF mRNA decay, effects not due to the destabilizing RNA binding protein tristetraprolin (TTP). Similar to its effects on TNF, CGP57380 caused dose-responsive inhibition of TTP production from stimulation with either LPS or CpG DNA. MNK inhibition also blocked IL-6 but permitted IL-10 production in response to LPS. Studies using bone marrow-derived macrophages (BMDM) isolated from a spontaneous mouse model of Crohn's disease-like ileitis (SAMP1/YitFc strain) revealed significant inhibition by CGP57380 of the proinflammatory cytokines TNF, IL-6, and monocyte chemoattractant protein-1 at 4 and 24 h after LPS stimulation. IL-10 production was higher in CGP53870-treated BMDM at 4 h but was similar to the controls by 24 h. Taken together, these data demonstrate that MNK kinases signal through a variety of TLR agonists and mediate a potent innate, proinflammatory cytokine response. 相似文献
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JK Sugden 《Biotechnic & histochemistry》2004,79(2):71-90
An overview of the basic principles of photochemistry is presented to facilitate discussion of fluorescence, quenching and quantum yields. These topics in turn provide the foundation for an account of fluorescence spectroscopy and its application to microscopy. A brief overview of light microscopy and the application of fluorescence microscopy is given. The influences of molecular features, such as aromatic character and substitution patterns, on color and fluorescence are described. The concept of color fading is considered with particular reference to its effect on microscopic preparations. A survey of representative fluorescent probes is provided, and their sensitivity, application, and limitations are described. The phototoxicity of fluorescent molecules is discussed using biomembranes and DNA as examples of targets of toxicity. Photodynamic therapy, a relatively new clinical application of phototoxicity, is described. Both anticancer and antimicrobial applications are noted, and an assessment is given of the current ideas on the ideal physicochemical properties of the sensitizing agents for such applications. 相似文献
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A comparison of the mechanisms of CO2 hydration by native and Co2+-substituted carbonic anhydrase II
We have measured the pH dependence of kcat and kcat/Km for CO2 hydration catalyzed by both native Zn2+-and metallo-substituted Co2+-bovine carbonic anhydrase II in the absence of inhibitory ions. For the Zn2+-enzyme, the pKa values controlling kcat and kcat/Km profiles are similar, but for the Co2+-enzyme the values are about 0.6 pH units apart. Computer simulations of a metal-hydroxide mechanism of carbonic anhydrase suggest that the data for both native and Co2+-carbonic anhydrase can be accounted for by the same mechanism of action, if we postulate that the substitution of Co2+ for Zn2+ in the active site causes a separation of about 0.6 pH units in the pKa values of His-64 and the metal-bound water molecule. We have also measured the activation parameters for kcat and kcat/Km for Co2+-substituted carbonic anhydrase II-catalyzed CO2 hydration and have compared these values to those obtained previously for the native Zn2+-enzyme. For kcat and kcat/Km we obtain an enthalpy of activation of 4.4 +/- 0.6 and approximately 0 kcal mol-1, respectively. The corresponding entropies of activation are -18 +/- 2 and -27 +/- 2 cal mol-1 K-1. 相似文献
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