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1.
Gbaguidi B Mazurkiewicz P Konings WN Driessen AJ Ruysschaert JM Vigano C 《Cellular and molecular life sciences : CMLS》2004,61(19-20):2646-2657
LmrP from Lactococcus lactis is a 45-kDa membrane protein that confers resistance to a wide variety of lipophilic compounds by acting as a proton motive force-driven efflux pump. This study shows that both the proton motive force and ligand interaction alter the accessibility of cytosolic tryptophan residues to a hydrophilic quencher. The proton motive force mediates an increase of LmrP accessibility toward the external medium and results in higher drug binding. Residues Asp128 and Asp68, from cytosolic loops, are involved in the proton motive force-mediated accessibility change. Ligand binding does not modify the protein accessibility, but the proton motive force-mediated restructuring is prerequisite for a subsequent accessibility change mediated by ligand binding. Asp142 cooperates with other membrane-embedded carboxylic residues to promote a conformational change that increases LmrP accessibility toward the hydrophilic quencher. This drug binding-mediated reorganization may be related to the transition between the high- and low-affinity drug-binding sites and is crucial for drug release in the extracellular medium. 相似文献
2.
Bartolomé F de Las Cuevas N Muñoz U Bermejo F Martín-Requero A 《Cellular and molecular life sciences : CMLS》2007,64(11):1437-1448
We have analyzed the intracellular signals that allow lymphoblasts from Alzheimer’s disease (AD) patients to escape from serum
deprivation-induced apoptosis. The following observations suggested that modulation of ERK1/2 activity by Ca2+/calmodulin (CaM) is involved in preventing apoptosis: (i) ERK1/2 activity seems to support lethality in control cells, as
PD98059, the inhibitor of the activating MEK prevented cell death; (ii) control cells show a persistent and higher stimulation
of ERK1/2 than that of AD cells in the absence of serum; (iii) CaM antagonists have no effects on control cells, but sensitize
AD cells to death induced by serum withdrawal and increased ERK1/2 phosphorylation, and (iv) no apoptotic effects of CaM antagonists
were observed in AD cells treated with PD98059. These results suggest the existence of an activation threshold of the ERK1/2
pathway setting by Ca2+/CaM-dependent mechanisms, which appears to be the critical factor controlling cell survival or death decision under trophic
factor withdrawal.
F. Bartolomé, N. de las Cuevas: These authors contributed equally to this work.
Received 14 February 2007; received after revision 16 April 2007; accepted 23 April 2007 相似文献
3.
Yoshida Y Obita T Kokusho Y Ohmura T Katayama T Ueda T Imoto T 《Cellular and molecular life sciences : CMLS》2003,60(9):1998-2008
DnaA protein binds specifically to a 9-base- pair motif called the DnaA box. Domain IV comprises 94 amino acid residues and is required for DNA binding. Using nuclear magnetic resonance analysis, we investigated the interaction between DnaA domain IV and both a DnaA box and a non-specific oligonucleotide that has a reduced affinity for DnaA. The 1H-15N HSQC spectrum of DnaA domain IV showed prominent chemical shift perturbations on six residues (Arg399, Ala404, Leu422, Asp433, Thr435 and Thr436) in the presence of the DnaA box. Through homology modeling, we located all of these residues on one side surface of the DnaA domain IV molecule. Moreover, we compared the chemical shift perturbation of the 1H-15N HSQC spectrum in the presence of the DnaA box with that in the presence of a non-specific oligonucleotide, and the results suggested that Leu422 imparts specificity in binding with the DnaA box.Received 6 May 2003; received after revision 18 June 2002; accepted 4 July 2003 相似文献
4.
5.
Plasticins belong to the dermaseptin superfamily of gene-encoded, membrane-active host defense peptides produced by the skin
of hylid frogs. The plasticins, which are rich in Gly and Leu residues arranged in regular 5-mer motifs GXXXG (where X is
any amino acid residue), have very similar amino acid sequences, hydrophobicities, and amphipathicities but differ markedly
in their net charge, conformational plasticity, and activity spectra. The intrinsic flexibility and structural malleability
of plasticins modulate their ability to bind to and disrupt the membranes of prokaryotic and eukaryotic cells, and/or to reach
intracellular targets, therefore triggering functional versatility. This family of closely related but functionally divergent
peptides constitutes a good model to address the relationships between structural polymorphism, membrane-interacting properties,
and the biological activity of antimicrobial, cell-penetrating, and viral fusion peptides. Plasticins could thus serve as
templates to design potent multifunctional drugs that could act simultaneously against bacterial pathogens and viruses.
Received 26 September 2007; received after revision 22 October 2007; accepted 29 October 2007 相似文献
6.
Ahlsén M Carlsson-Skwirut C Jonsson AP Cederlund E Bergman T Bang P 《Cellular and molecular life sciences : CMLS》2007,64(14):1870-1880
Proteolytic cleavage of insulin-like growth factor (IGF) binding protein (IGFBP)-3 during pregnancy is likely to have both
IGF-dependent and -independent effects on maternal, placental and fetal growth and metabolism. A 30-kDa proteolytic IGFBP-3
fragment was isolated from third trimester pregnancy human serum and identified by N- and C-terminal amino acid sequence analysis
and mass spectrometry to correspond to residues 1–212 of the parent protein. This fragment is the dominating IGFBP-3 immunoreactive
species in pregnancy serum. The 30-kDa fragment was also detected in serum of non-pregnant women where it coexists with intact
IGFBP-3. Using biosensor technology, (1–212)IGFBP-3 was found to have 11-fold lower affinity for IGF-I compared to intact
IGFBP-3, while a 4-fold decrease in affinity was found for IGF-II. Tests with des(1–3)IGF-I suggest fast binding of IGF-I
to the N-terminal region of IGFBP-3 and similar affinity to a slow binding site in the C-terminal region.
Received 24 April 2007; received after revision 11 June 2007; accepted 13 June 2007 相似文献
7.
Jägerbrink T Lexander H Palmberg C Shafqat J Sharoyko V Berggren PO Efendic S Zaitsev S Jörnvall H 《Cellular and molecular life sciences : CMLS》2007,64(10):1310-1316
The effects of an imidazoline compound (BL11282) on protein expression in rat pancreatic islets were investigated with a proteomic
approach. The compound increases insulin release selectively at high glucose concentrations and is therefore of interest in
type 2 diabetes. Whole cell extracts from isolated drug-treated and native pancreatic rat islets were compared after separation
by 2-D gel electrophoresis. Differentially expressed proteins were identified by mass spectrometry; 15 proteins were selectively
up-regulated and 7 selectively down-regulated in drug-treated islets. Of special interest among the differentially expressed
proteins are those involved in protein folding (Hsp60, protein disulfide isomerase, calreticulin), Ca2+ binding (calgizzarin, calcyclin and annexin I) and metabolism or signalling (pyruvate kinase, alpha enolase and protein kinase
C inhibitor 1).
Received 19 March 2007; received after revision 11 April 2007; accepted 11 April 2007 相似文献
8.
Hunt MC Greene S Hultenby K Svensson LT Engberg S Alexson SE 《Cellular and molecular life sciences : CMLS》2007,64(12):1558-1570
Acyl-CoA thioesterases (ACOTs) catalyze the hydrolysis of acyl-CoAs to free fatty acids and coenzyme A. Recent studies have
demonstrated that one gene named Acot7, reported to be mainly expressed in brain and testis, is transcribed in several different isoforms by alternative usage of
first exons. Strongly decreased levels of ACOT7 activity and protein in both mitochondria and cytosol was reported in patients
diagnosed with fatty acid oxidation defects, linking ACOT7 function to regulation of fatty acid oxidation in other tissues.
In this study, we have identified five possible first exons in mouse Acot7 (Acot7a–e) and show that all five first exons are transcribed in a tissue-specific manner. Taken together, these data show that the
Acot7 gene is expressed as multiple isoforms in a tissue-specific manner, and that expression in tissues other than brain and testis
is likely to play important roles in fatty acid metabolism.
Received 5 February 2007: received after revision 3 April 2007; accepted 19 April 2007 相似文献
9.
Daly JW 《Cellular and molecular life sciences : CMLS》2007,64(16):2153-2169
Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine
and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played
key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological
processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic
agents for intervention in Alzheimer’s disease, asthma, cancer, diabetes, and Parkinson’s disease. Such compounds also have
activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse
effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.
Received 31 January 2007; received after revision 7 April 2007; accepted 26 April 2007 相似文献
10.
Computational inhibitor design against malaria plasmepsins 总被引:1,自引:1,他引:0
Bjelic S Nervall M Gutiérrez-de-Terán H Ersmark K Hallberg A Aqvist J 《Cellular and molecular life sciences : CMLS》2007,64(17):2285-2305
Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by
the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains
that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I–IV in view of the
interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin
II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational
techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial
plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have
been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations
is analyzed.
S. Bjelic, M. Nervall: These authors contributed equally to this work.
Received 27 February 2007; received after revision 17 April 2007; accepted 26 April 2007 相似文献
11.
Isakovic A Harhaji L Stevanovic D Markovic Z Sumarac-Dumanovic M Starcevic V Micic D Trajkovic V 《Cellular and molecular life sciences : CMLS》2007,64(10):1290-1302
The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density
cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G0/G1 phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction
of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and
oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition
(cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis
(sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C,
an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed
in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic
action of metformin.
Received 14 February 2007; received after revision 26 March 2007; accepted 3 April 2007 相似文献
12.
Sharoyko VV Zaitseva II Leibiger B Efendić S Berggren PO Zaitsev SV 《Cellular and molecular life sciences : CMLS》2007,64(22):2985-2993
The mechanism by which the novel, pure glucose-dependent insulinotropic, imidazoline derivative BL11282 promotes insulin secretion
in pancreatic islets has been investigated. The roles of KATP channels, α2-adrenoreceptors, the I1-receptor-phosphatidylcholine-specific phospholipase (PC-PLC) pathway and arachidonic acid signaling in BL11282 potentiation
of insulin secretion in pancreatic islets were studied. Using SUR1(-/-) deficient mice, the previous notion that the insulinotropic activity of BL11282 is not related to its interaction with KATP channels was confirmed. Insulinotropic activity of BL11282 was not related to its effect on α2-adrenoreceptors, I1-imidazoline receptors or PC-PLC. BL11282 significantly increased [3H]arachidonic acid production. This effect was abolished in the presence of the iPLA2 inhibitor, bromoenol lactone. The data suggest that potentiation of glucose-induced insulin release by BL11282, which is
independent of concomitant changes in cytoplasmic free Ca2+ concentration, involves release of arachidonic acid by iPLA2 and its metabolism to epoxyeicosatrienoic acids through the cytochrome P-450 pathway.
Received 5 July 2007; received after revision 18 September 2007; accepted 20 September 2007 相似文献
13.
Evaluation of models for the mechanism of action of 4-hydroxyphenylpyruvate dioxygenase 总被引:1,自引:0,他引:1
Summary 4-Hydroxyphenylpyruvic acid was oxygenated with various complexes of oxygen with Fe2+, superoxide ion, hydroperoxide anion, triplet and singlet oxygen. Oxidation occurred giving varying amounts of the 4-hydroxy derivatives of benzaldehyde, benzoic acid, phenol, phenylacetic acid and 4-carboxymethylquinone, but no homogentisic acid. 4-Hydroxyphenylperacetic acid was prepared and shown not to undergo self-oxidation. Its ferrous salt decomposed to 4-hydroxybenzyl alcohol. It is concluded that thea-keto carboxylic function is the site of oxygenation in the enzyme process and that a trioxalanone rather than a peracid intermediate may be implicated.Acknowledgments. We thank a referee for drawing our attention to the work of Hawkinsin and we are indebted to the Swiss National Science Foundation for the support of this work (grant No 2.418.0.79). 相似文献
14.
Ueno K Ueda T Sakai K Abe Y Hamasaki N Okamoto M Imoto T 《Cellular and molecular life sciences : CMLS》2005,62(2):199-205
We examined chemical reactions in mouse lysozyme after incubation under physiological conditions (pH 7 and 37°C). After incubation for 8 weeks, racemization was observed specifically at Asn127 among the 19 Asp/Asn residues in mouse lysozyme. Furthermore, analysis of the primary structure showed that the racemized residue was not Asp, but Asn, which demonstrates that deamidation and isomerization did not occur. These results mean that this racemization occurs without forming a succinimide intermediate. This is the first example of D-asparaginyl formation in a protein occurring during the racemization process under physiological conditions.Received 16 September 2004; received after revision 26 October 2004; accepted 12 November 2004 相似文献
15.
Hurtaud C Gelly C Chen Z Lévi-Meyrueis C Bouillaud F 《Cellular and molecular life sciences : CMLS》2007,64(14):1853-1860
Uncoupling protein 2 (UCP2) belongs to a family of transporters/exchangers of the mitochondrial inner membrane. Using cell
lines representing natural sites of UCP2 expression (macrophages, colonocytes, pancreatic beta cells), we show that UCP2 expression
is stimulated by glutamine at physiological concentrations. This control is exerted at the translational level. We demonstrate
that the upstream open reading frame (ORF1) in the 5’ untranslated region (5’UTR) of the UCP2 mRNA is required for this stimulation
to take place. Cloning of the 5’ UTR of the UCP2 mRNA in front of a GFP cDNA resulted in a reporter gene with which GFP expression
could be induced by glutamine. An effect of glutamine on translation of a given mRNA has not been identified before, and this
is the first evidence for a link between UCP2 and glutamine, an amino acid oxidized by immune cells or intestinal epithelium
and playing a role in the control of insulin secretion.
Received 26 January 2007; received after revision 16 April 2007; accepted 8 May 2007
C. Hurtaud, C. Gelly: These authors contributed equally to this work. 相似文献
16.
Summary The common bile duct of male Sprague-Dawley rats was cannulated with either PE 10 or PE 50 tubing. Maximal secretory rate of taurocholate averaged 389±67 (SD) and 657±115 nmoles·min–1·g liver–1 in the PE 10 and PE 50 group, respectively (p<0.005). Maximal bile secretory pressure was significantly higher in the PE 10 group (240±28 vs 174±8 mm H20; p<0.005). When the maximal secretory rate was exceeded, bile flow decreased in both groups but this was accompanied with a decrease in maximal bile secretory pressure in the PE 10 group only. Maximal secretory rate of bile salts is markedly influenced by experimental technique. Use of small caliber common bile duct cannulae leads to partial obstruction and decreases the apparent maximal secretory rate for taurocholate.Acknowledgments. J. Reichen was the recipient of a Faculty Development Award in Clinical Pharmacology from The Pharmaceutical Manufacturer's Association Foundation, and is the recipient of a Research Career Development Award (KO4 AM 1189) from the National Institutes of Health. Supported by National Institutes of Health grant RO1 AM 27597. 相似文献
17.
Venkatesan A Nath A Ming GL Song H 《Cellular and molecular life sciences : CMLS》2007,64(16):2120-2132
New dentate granule cells are continuously generated from neural progenitor cells and integrated into the existing hippocampal
circuitry in the adult mammalian brain through an orchestrated process termed adult neurogenesis. While the exact function
remains elusive, adult neurogenesis has been suggested to play important roles in specific cognitive functions. Adult hippocampal
neurogenesis is regulated by a variety of physiological and pathological stimulations. Here we review emerging evidence showing
that HIV infection and several drugs of abuse result in molecular changes that may affect different aspects of adult hippocampal
neurogenesis. These new findings raise the possibility that cognitive dysfunction in the setting of HIV infection or drug
abuse may, in part, be related to alterations in hippocampal neurogenesis. A better understanding of how HIV and drugs of
abuse affect both molecular and cellular aspects of adult neurogenesis may lead to development of more effective therapeutic
interventions for these interlinked epidemics.
Received 6 February 2007; received after revision 26 March 2007; accepted 25 April 2007 相似文献
18.
B Croizat F Berthelot B Ferrandes P Eymard C Sahuquillo 《Comptes rendus des séances de l'Académie des sciences. Série D, Sciences naturelles》1979,289(16):1283-1286
We describe the induction of neuroblastoma morphological differentiation by 1 methyl cyclohexane carboxylic acid (CCA) and by some C1 derivatives of CCA. This induction proceeds in a medium which allows, in the absence of inducer, a normal growth of neuroblastoma cells and contains 7.5% fetal Calf serum. In order to establish a clear-dose response relationship and to compare the relative potencies of different drugs, the morphological changes were assessed by examining "long neurite-bearing cells". 相似文献
19.
Unique evolution of Bivalvia arginine kinases 总被引:1,自引:0,他引:1
Takeuchi M Mizuta C Uda K Fujimoto N Okamoto M Suzuki T 《Cellular and molecular life sciences : CMLS》2004,61(1):110-117
The clams Pseudocardium, Solen, Corbicula and Ensis possess a unique form of arginine kinase (AK) with a molecular mass of 80 kDa and an unusual two-domain structure, a result of gene duplication and subsequent fusion. These AKs also lack two functionally important amino acid residues, Asp62 and Arg193, which are strictly conserved in other 40-kDa AKs and are assumed to be key residues for stabilizing the substrate-bound structure. However, these AKs show higher enzyme activity. The cDNA-derived amino acid sequences of 40-kDa AKs from the blood clam Scapharca broughtonii and the oyster Crassostrea gigas were determined. While Asp62 and Arg193 are conserved in Scapharca AK, these two key residues are replaced by Asn and Lys, respectively, in Crassostrea AK. The native enzyme from Crassostrea and both of the recombinant enzymes show an enzyme activity similar to that of two-domain clam AKs and at least twofold higher than that of other molluskan AKs. Although the replacement of Asp62 or Arg193 by Gly in normal AK causes a considerable decrease in Vmax (6–15% of wild-type enzyme) and a two- to threefold increase in Km for arginine, the same replacement in Scapharca AK had no pronounced effect on enzyme activity. Together with the observation that bivalve AKs are phylogenetically distinct from other molluskan AKs, these results suggest that bivalve AKs have undergone a unique molecular evolution; the characteristic stabilizing function of residues 62 and 193 has been lost and, consequently, the enzyme shows higher activity than normal.Received 14 October 2003; accepted 1 November 2003 相似文献
20.
Pozza A Perez-Victoria JM Sardo A Ahmed-Belkacem A Di Pietro A 《Cellular and molecular life sciences : CMLS》2006,63(16):1912-1922
Human ABCG2 was efficiently overexpressed in insect cell membranes, solubilized with 3-[(3-cholamidopropyl)dimethyl ammonio]-1-propanesulfonate,
and purified through N-terminal hexahistidine tag. Its functionality was assessed by high vanadate-sensitive ATPase activity, and nucleotide-binding
capacity. Interestingly, the R482T point mutation increased both maximal hydrolysis rate and affinity for MgATP, and lowered
sensitivity to vanadate inhibition. Direct nucleotide binding, as monitored by quenching of intrinsic fluorescence, indicated
a mutation-related preference for ATP over ADP. The R482T mutation only produced a limited change, if any, on the binding
of drug substrates, indicating that methotrexate, on the one hand, and rhodamine 123 or doxorubicin, on the other hand, bound
similarly to wild-type and mutant transporters whether or not they were subject to cellular transport. In addition, the characteristic
inhibitors GF120918 and 6-prenylchrysin, which alter mitoxantrone efflux much better for wild-type than mutant ABCG2, bound
similarly to purified ABCG2, while the highly-potent Ko143 bound in the nanomolar range also effective in inhibition of drug
transport. All results indicate that the role of the arginine-482 mutation on substrate drug transport and inhibitor efficiency
is not mediated by changes in drug binding.
Received 10 April 2006; received after revision 22 May 2006; accepted 12 June 2006
A. Pozza and J. M. Perez-Victoria contributed equally to this work 相似文献