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11.
Physical mechanism for regulation of proton solute symport in Escherichia coli. 总被引:5,自引:0,他引:5 下载免费PDF全文
W N Konings G T Robillard 《Proceedings of the National Academy of Sciences of the United States of America》1982,79(18):5480-5484
The activity of the Escherichia coli transport proteins for lactose and proline can be altered by changing the redox state of the dithiols in these carriers. A series of lipophilic oxidizing agents has been shown to inhibit and subsequent addition of dithiothreitol to restore full activity. Both systems are irreversibly inhibited by N-ethylmaleimide, but prior addition of oxidizing agents protects against this inhibition. These data, as well as studies on the inhibitory effect of the dithiol-specific reagent phenylarsine oxide, show that the redox-sensitive step is the conversion of a dithiol to a disulfide. Measurement of the initial rate as a function of the lactose and L-proline concentrations shows that the oxidation of a dithiol to a disulfide increases the Km of the carriers for lactose and L-proline. The reduced (dithiol) form of the carrier has a low Km and the oxidized (disulfide) form has a high Km for its substrate. The changes in Km brought about by reduction and oxidation are the same as those that accompany the generation and dissipation, respectively, of an electrochemical proton gradient (delta mu H+). These results support a mechanism in which an delta mu H+ or one of its components alters the ligand affinities of the carrier during a single transport cycle through conversion from the reduced to the oxidized form. 相似文献
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Protease mutations in HIV-1 non-B strains infecting drug-naive villagers in Cameroon 总被引:1,自引:0,他引:1
Konings FA Zhong P Agwara M Agyingi L Zekeng L Achkar JM Ewane L Saa Afane Ze E Kinge T Nyambi PN 《AIDS research and human retroviruses》2004,20(1):105-109
To describe the presence of protease inhibitor (PI) resistance-associated mutations and subtype distribution in drug-naive villagers of six provinces of Cameroon, we sequenced the protease (PR) gene (297 bp) of 128 viruses. Secondary PI resistance-associated mutations were identified at five sites: L10I/V (16%), K20R (8%), M36I (98%), L63P (13%), and V77I (6%). No primary mutation in the PR was identified. Of the 128 specimens analyzed, subtypes A (11%), C(2%), D (6%), F2 (3%), G (6%), H (0.8%), J (6%), and CRF02_AG (60%) were identified. The mutations identified were not characteristic to any particular subtype. The absence of primary mutations, in addition to the few secondary mutations, gives good perspectives for PI treatment interventions in these rural areas. 相似文献
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Judith V. E. Hettinga Willy Lemstra Coby Meijer Gerrit Los Elisabeth G. E. de Vries Antonius W. T. Konings Harm H. Kampinga 《International journal of cancer. Journal international du cancer》1996,67(6):800-807
It has been suggested that the expression of certain heat-shock proteins (HSPs) may be prognostic markers in several tumor types. Since HSPs may be involved in determining cellular sensitivity to chemotherapeutic drugs, the possible relation between HSP expression and cisplatin (cDDP) sensitivity was studied. Three human germ-cell tumor cell lines, 1 human small-cell lung carcinoma (SCLC) cell line and 3 human colon carcinoma cell lines were used as a model for differences in intrinsic cDDP sensitivity. The constitutive expression of a panel of HSPs was studied by immunoblotting. No correlation was found between expression of HSP90, HSP73, HSP72, HSP60 and HSP27 and the extent of intrinsic cDDP sensitivity when all cell lines studied were considered. However, for the 3 cell lines derived from germ-cell carcinomas, HSP27 expression was inversely related to cDDP sensitivity, i.e. decreased HSP27 levels were associated with decreased sensitivity. Constitutive HSP expression was also studied in 2 sets of human cell lines with in vitro acquired cDDP resistance. In both resistant cell lines, decreased expression of HSP27 (as determined by Western blotting) was found as compared to the sensitive parent cell lines. Thus, acquired resistance to cDDP was also accompanied by decreased HSP27 expression. Interestingly, when basal HSP27 mRNA levels were measured in the SCLC cell line (GLC4) and its subline with acquired resistance (GLC4-cDDP), no significant differences were detected. Continuous cDDP incubation increased HSP27 levels and induced HSP27 phosphorylation in GLC4 cells, but not in the resistant subline. Thus, although no general relationships between HSP expression and cDDP sensitivity are apparent, high HSP27 expression in vitro relates to high sensitivity to cDDP treatment in some tumor types. This is in accordance with reported clinical data on high HSP27 levels in tumors correlating with good prognosis. © 1996 Wiley-Liss, Inc. 相似文献
16.
Aron C. Beekman Herman J. Woerdenbag Harm H. Kampinga Antonius W. T. Konings 《Phytotherapy research : PTR》1996,10(2):140-144
Artemisinin and its derivatives possess an endoperoxide bridge, which is thought to lead to the production of free-radical species. The cytotoxicity of some of these agents to a murine Ehrlich ascites (EN19) and a human HeLa S3 cancer cell line was determined using the MTT and the clonogenic assay. The MTT assay cannot distinguish between growth inhibition and cell killing, while the clonogenic assay detects actual cell death. The use of both assays to test a certain drug may give information on the mode of its cytotoxicity (i.e. growth inhibition versus cell killing). The endoperoxides artemisinin and the dimer of dihydroartemisinin showed much higher cytotoxicity in the MTT assay compared with the clonogenic assay. Thus these drugs mainly induced growth inhibition. For artemisitene and eupatoriopicrin, which possess an exocyclic methylene with alkylating properties, both tests yielded comparable results. For these compounds the MTT assay merely determined cell killing. For the reference drugs cisplatin and doxorubicin the MTT assay showed lower cytotoxicity than the clonogenic assay. This may be explained by the metabolic activity of cells that were clonogenically dead. Moreover, our experiments have shown that the MTT assay may lead to misinterpretations concerning the mode of action of certain drugs, when it is used as a substitute for the clonogenic assay. 相似文献
17.
Overbeek Kasper A. Cahen Djuna L. Kamps Anne Konings Ingrid C. A. W. Harinck Femme Kuenen Marianne A. Koerkamp Bas Groot Besselink Marc G. van Eijck Casper H. Wagner Anja Ausems Margreet G. E. van der Vlugt Manon Fockens Paul Vleggaar Frank P. Poley Jan-Werner van Hooft Jeanin E. Bleiker Eveline M. A. Bruno Marco J. 《Familial cancer》2020,19(3):247-258
Familial Cancer - In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our... 相似文献
18.
Cell-biologic and functional analyses of five new Aquaporin-2 missense mutations that cause recessive nephrogenic diabetes insipidus 总被引:3,自引:0,他引:3
Marr N Bichet DG Hoefs S Savelkoul PJ Konings IB De Mattia F Graat MP Arthus MF Lonergan M Fujiwara TM Knoers NV Landau D Balfe WJ Oksche A Rosenthal W Müller D Van Os CH Deen PM 《Journal of the American Society of Nephrology : JASN》2002,13(9):2267-2277
Mutations in the Aquaporin-2 gene, which encodes a renal water channel, have been shown to cause autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Most AQP2 missense mutants in recessive NDI are retained in the endoplasmic reticulum (ER), but AQP2-T125M and AQP2-G175R were reported to be nonfunctional channels unimpaired in their routing to the plasma membrane. In five families, seven novel AQP2 gene mutations were identified and their cell-biologic basis for causing recessive NDI was analyzed. The patients in four families were homozygous for mutations, encoding AQP2-L28P, AQP2-A47V, AQP2-V71M, or AQP2-P185A. Expression in oocytes revealed that all these mutants, and also AQP2-T125M and AQP2-G175R, conferred a reduced water permeability compared with wt-AQP2, which was due to ER retardation. The patient in the fifth family had a G>A nucleotide substitution in the splice donor site of one allele that results in an out-of-frame protein. The other allele has a nucleotide deletion (c652delC) and a missense mutation (V194I). The routing and function of AQP2-V194I in oocytes was not different from wt-AQP2; it was therefore concluded that c652delC, which leads to an out-of-frame protein, is the NDI-causing mutation of the second allele. This study indicates that misfolding and ER retention is the main, and possibly only, cell-biologic basis for recessive NDI caused by missense AQP2 proteins. In addition, the reduced single channel water permeability of AQP2-A47V (40%) and AQP2-T125M (25%) might become of therapeutic value when chemical chaperones can be found that restore their routing to the plasma membrane. 相似文献
19.
Paulussen A Lavrijsen K Bohets H Hendrickx J Verhasselt P Luyten W Konings F Armstrong M 《Pharmacogenetics》2000,10(5):415-424