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1.
Responsiveness to Exogenous Camp of a Saccharomyces Cerevisiae Strain Conferred by Naturally Occurring Alleles of Pde1 and Pde2 总被引:2,自引:0,他引:2
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H. Mitsuzawa 《Genetics》1993,135(2):321-326
The Saccharomyces cerevisiae strain P-28-24C, from which cAMP requiring mutants derived, responded to exogenously added cAMP. Upon the addition of cAMP, this strain showed phenotypes shared by mutants with elevated activity of the cAMP pathway. Genetic analysis involving serial crosses of this strain to a strain with another genetic background revealed that the responsiveness to cAMP results from naturally occurring loss-of-function alleles of PDE1 and PDE2, which encode low and high affinity cAMP phosphodiesterases, respectively. In addition, P-28-24C was found to carry a mutation conferring slow growth that lies in CYR1, which encodes adenylate cyclase, and the slow growth phenotype caused by the cyr1 mutation was suppressed by the pde2 mutation. Therefore P-28-24C is fortuitously a pde1 pde2 cyr1 triple mutant. Responsiveness to cAMP conferred by pde mutations suggests that S. cerevisiae cells are permeable to cAMP to some extent and that the apparent absence of effect of exogenously added cAMP on wild-type cells is due to immediate degradation by cAMP phosphodiesterases. 相似文献
2.
Jaumann M Dettling J Gubelt M Zimmermann U Gerling A Paquet-Durand F Feil S Wolpert S Franz C Varakina K Xiong H Brandt N Kuhn S Geisler HS Rohbock K Ruth P Schlossmann J Hütter J Sandner P Feil R Engel J Knipper M Rüttiger L 《Nature medicine》2012,18(2):252-259
Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL. 相似文献
3.
The mollu-series glycosphingolipids, O-alpha-D-mannopyranosyl-(1----3)-O-beta-D-mannopyranosyl-(1----4)-O-bet a-D-glucopyranosyl-(1----1)-2-N-tetracosanoyl-(4E)-sphingeni ne and O-alpha-D-mannopyranosyl-(1----3)-O-[beta-D-xylopyranosyl-(1----2])-O- beta-D-mannopyranosyl-(1----4)-O-beta-D-glucopyranosyl-(1----1)-2-N- tetracosanoyl-(4E)-sphingenine, were synthesized for the first time by using 2,3,4-tri-O-acetyl-D-xylopyranosyl trichloroacetimidate, methyl 2,3,4,6-tetra-O-acetyl-1-thio-alpha-D-mannopyranoside, benzyl O-(4,6-di-O-benzyl-beta-D-mannopyranosyl)-(1----4)-2,3,6-tri-O-benzyl-be ta-D- glucopyranoside 9, and (2S,3R,4E)-2-azido-3-O-(tert-butyldiphenylsilyl)-4-octade cene-1,3-diol 6 as the key intermediates. The hexa-O-benzyl disaccharide 9 was prepared by coupling two monosaccharide synthons, namely, 2,3-di-O-allyl-4,6-di-O-benzyl-alpha-D-mannopyranosyl bromide and benzyl 2,3,6-tri-O-benzyl-beta-D-glucopyranoside. It was demonstrated that azide 6 was highly efficient as a synthon for the ceramide part in the coupling with both glycotriaosyl and glycotetraosyl donors, particularly in the presence of trimethylsilyl triflate. 相似文献
4.
David B. Morton Rachel Clemens-Grisham Dennis J. Hazelett Anke Vermehren-Schmaedick 《Genetics》2010,186(1):159-165
Pde1c is a calcium/calmodulin-regulated, dual-specificity cyclic nucleotide phosphodiesterase. We have used a transposon insertion line to investigate the physiological function of Pde1c in Drosophila melanogaster and to show that the insertion leads to male sterility and male mating behavior defects that include reduced copulation rates. Sterility appears to be primarily due to elimination of sperm from the female reproductive system. The male mating behavior defects were fully rescued by expression of exogenous Pde1c under the control of either a Pde1c or a pan-neuronal promoter, whereas the sterility could be only partially rescued by expression of exogenous Pde1c under the control of these promoters. We also show that Pde1c has a male-specific expression pattern in the CNS with an increased number of Pde1c-expressing neurons in the abdominal ganglion in males.THE cyclic nucleotides, cyclic AMP (cAMP) and cyclic GMP (cGMP), have been known for many years to regulate a wide variety of physiological processes in all animals (e.g., Siegel et al. 1994). Similarly, there is a large body of research focused on an understanding of the structure and regulation of the enzymes that synthesize cAMP and cGMP, the adenylyl and guanylyl cyclases, respectively. Although the concentrations of cyclic nucleotides within a cell are regulated by both their synthesis and their degradation, less attention has been devoted to the function and regulation of the enzymes that break down cyclic nucleotides, the phosphodiesterases (PDEs).Mammals have >20 genes that code for cyclic nucleotide PDEs, which have been subdivided into 11 families on the basis of their sequences, substrate specificities, and regulatory properties (Conti and Beavo 2007). Insects also have a wide variety of PDEs with Drosophila melanogaster containing 6 genes that code for cyclic nucleotide PDEs (Morton and Hudson 2002; Day et al. 2005). On the basis of their sequence similarity to the mammalian PDEs, these 6 genes have been classified into 6 of the 11 families: Pde1c, Pde4, Pde6, Pde8, Pde9, and Pde11 (Day et al. 2005). When their biochemical properties have been investigated, they match well with other members of the same family (Day et al. 2005).Despite the importance of cyclic nucleotides in insect physiology, only one of the Drosophila PDEs has been associated with a mutant phenotype. This gene, Pde4, also known as dunce, was one of the first learning and memory mutants discovered (Byers et al. 1981; Davis et al. 1995). In this study, we have investigated the phenotypes associated with reduced expression of Pde1c, a PDE that has dual specificity for both cAMP and cGMP and that is stimulated in the presence of calcium and calmodulin (Day et al. 2005). Here we show that Pde1c is required for male fertility and male mating behavior. Male sterility appears to be primarily due to females rejecting sperm or failing to store the sperm from mutant males. 相似文献
5.
L Wang Y Jia H Rogers YP Wu S Huang CT Noguchi 《The Journal of biological chemistry》2012,287(36):30157-30169
Erythropoietin (EPO), the cytokine required for erythrocyte production, contributes to muscle progenitor cell proliferation and delay myogenic differentiation. However, the underlying mechanism is not yet fully understood. Here, we report that EPO changes the skeletal myogenic regulatory factor expression program and delays differentiation via induction of GATA-4 and the basic helix-loop-helix TAL1 and that knockdown of both factors promotes differentiation. EPO increases the Sirt1 level, a NAD(+)-dependent deacetylase, and also induces the NAD(+)/NADH ratio that further increases Sirt1 activity. Sirt1 knockdown reduced GATA-4 and TAL1 expression, impaired EPO effect on delayed myogenic differentiation, and the Sirt1 knockdown effect was abrogated when combined with overexpression of GATA-4 or TAL1. GATA-4 interacts with Sirt1 and targets Sirt1 to the myogenin promoter and represses myogenin expression, whereas TAL1 inhibits myogenin expression by decreasing MyoD binding to and activation of the myogenin promoter. Sirt1 was found to bind to the GATA-4 promoter to directly regulate GATA-4 expression and GATA-4 binds to the TAL1 promoter to regulate TAL1 expression positively. These data suggest that GATA-4, TAL1, and Sirt1 cross-talk each other to regulate myogenic differentiation and mediate EPO activity during myogenic differentiation with Sirt1 playing a role upstream of GATA-4 and TAL1. Taken together, our findings reveal a novel role for GATA-4 and TAL1 to affect skeletal myogenic differentiation and EPO response via cross-talk with Sirt1. 相似文献
6.
Liotta LJ Capotosto RD Garbitt RA Horan BM Kelly PJ Koleros AP Brouillette LM Kuhn AM Targontsidis S 《Carbohydrate research》2001,331(3):247-253
The syntheses of methyl alpha-D-glucopyranosyl-(1-->4)-alpha-D-galactopyranoside (1) and methyl alpha-D-xylo-hex-4-ulopyranosyl-(1-->4)-alpha-D-galactopyranoside (4) are reported. The keto-disaccharide 4 is of interest in our design, synthesis, and study of pectate lyase inhibitors. The key step in the syntheses was the high-yielding, stereospecific formation of methyl 4,6-O-benzylidene-2',3'-di-O-benzyl-alpha-D-glucopyranosyl-(1-->4)-2,3,6-tri-O-benzyl-alpha-D-galactopyranoside (15), which was accomplished by reacting 2,3-di-O-benzyl-4,6-O-benzylidene-D-glucopyranosyl trichloroacetimidate (10) with methyl 2,3,6-tri-O-benzyl-alpha-D-galactopyranoside (14) in the presence of a catalytic amount of tert-butyldimethylsilyl trifluoromethane sulfonate (TMSOTF). Compound 15 was either hydrogenolyzed to yield disaccharide 1 or treated with NaBH3CN-HCl in 1:1 tetrahydrofuran-ether to yield methyl 2,3,6-tri-O-benzyl-alpha-D-glucopyranosyl-(1-->4)-2,3,6-tri-O-benzyl-alpha-D-galactopyranoside (2). The free 4'-OH of compound 2 was oxidized to a carbonyl group by a Swern oxidation, and the protecting groups were removed by hydrogenolysis to yield keto-disaccharide 4. These synthetic pathways were simple, yet high yielding. 相似文献
7.
Linus S Lin Thomas Lanza Ermenegilda McCauley Gail Van Riper Usha Kidambi Jin Cao Linda A Egger Richard A Mumford John A Schmidt Malcolm MacCoss William K Hagmann 《Bioorganic & medicinal chemistry letters》2002,12(2):133-136
N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the alpha(4)beta(1) integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for alpha(4)beta(1) and alpha(4)beta(7) is proposed to explain the structure-activity relationship. 相似文献
8.
Seung Kyoon Woo Min Seong Kwon Alexander Ivanov Volodymyr Gerzanich J. Marc Simard 《The Journal of biological chemistry》2013,288(5):3655-3667
The sulfonylurea receptor 1 (Sur1)-NCCa-ATP channel plays a central role in necrotic cell death in central nervous system (CNS) injury, including ischemic stroke, and traumatic brain and spinal cord injury. Here, we show that Sur1-NCCa-ATP channels are formed by co-assembly of Sur1 and transient receptor potential melastatin 4 (Trpm4). Co-expression of Sur1 and Trpm4 yielded Sur1-Trpm4 heteromers, as shown in experiments with Förster resonance energy transfer (FRET) and co-immunoprecipitation. Co-expression of Sur1 and Trpm4 also yielded functional Sur1-Trpm4 channels with biophysical properties of Trpm4 and pharmacological properties of Sur1. Co-assembly with Sur1 doubled the affinity of Trpm4 for calmodulin and doubled its sensitivity to intracellular calcium. Experiments with FRET and co-immunoprecipitation showed de novo appearance of Sur1-Trpm4 heteromers after spinal cord injury in rats. Our findings depart from the long-held view of an exclusive association between Sur1 and KATP channels and reveal an unexpected molecular partnership with far-ranging implications for CNS injury. 相似文献
9.
Nicole R. Miller R. Nathan Daniels David Lee P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(7):2174-2177
This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of a novel series of selective M1 mAChR antagonists, based on an N-(4-(4-alkylpiperazin-1-yl)phenyl)benzamide scaffold for the potential treatment of Parkinson’s disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC50s in the 350 nM to >10 μM range with varying degrees of functional selectivity versus M2–M5. 相似文献
10.
1-O-(4-Decyloxymethylphenyl)- and 1-O-(4-decyloxyphenylmethyl)-2-O-acetyl-glycero-3-phosphorylcholin e were synthesized from 2,2-dimethyl-1,3-dioxolane-4-methanol. The utility of a 2-O-tetrahydropyranyl ether as a protecting group and its facile removal in the presence of a 3-phosphorylcholine is illustrated. 相似文献
11.
Watanabe H Nishimoto T Sonoda T Kubota M Chaen H Fukuda S 《Carbohydrate research》2006,341(8):957-963
A bacterial strain AM7, isolated from soil and identified as Bacillus circulans, produced two kinds of novel cyclic oligosaccharides. The cyclic oligosaccharides were produced from amylose using a culture supernatant of the strain as the enzyme preparation. The major product was a cyclomaltopentaose cyclized by an alpha-(1-->6)-linkage, cyclo-{-->6)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->}. The other minor product was cyclomaltohexaose cyclized by an alpha-(1-->6)-linkage, cyclo-{-->6)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->4)-alpha-D-Glcp-(1-->}. We propose the names isocyclomaltopentaose (ICG5) and isocyclomaltohexaose (ICG6) for these novel cyclic maltooligosaccharides having one alpha-(1-->6)-linkage. ICG5 was digested by alpha-amylase derived from Aspergillus oryzae, cyclomaltodextrin glucanotransferase (CGTase) from Bacillus stearothermophilus, and maltogenic alpha-amylase. On the other hand, ICG6 was digested by CGTase from B. stearothermophilus and B. circulans, and maltogenic alpha-amylase. This is the first report of enzymatically produced cyclomaltopentaose and cyclomaltohexaose, which have an alpha-(1-->6)-linkage in their molecules. 相似文献
12.
The tetrasaccharide a-D-Glcp-(1----4)-a-D-Xylp-(1----4)-a-D-Xylp-(1----4)-D- Glcp (1) has been synthesized, as a substrate analogue of alpha amylase, by silver perchlorate-catalyzed glycosylation of benzyl 2,3,6-tri-O-benzyl-4-O-(2,3-di-O-benzyl-a-D-xylopyranosyl)-beta-D- glucopyranoside (30) with 2,3-di-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-a-D- glucopyranosyl)-a-D-xylopyranosyl chloride or by methyl triflate-promoted condensation of 30 with methyl 2,3-di-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl)-1-thio- beta-D-xylopyranoside, followed by removal of protecting groups of the resulting tetrasaccharide derivative 40. 相似文献
13.
Purification of Shiga toxin by alpha-D-galactose-(1----4)-beta-D-galactose-(1----4)-beta-D-glucose-(1- ---) receptor ligand-based chromatography 总被引:1,自引:0,他引:1
A simple and rapid method for Shiga toxin purification based on specific binding to the Gal alpha 1----4Gal beta 1----4Glc globotrioside trisaccharide covalently linked to polyacryl/polyvinyl (Fractogel) has been developed. A cell-free sonicate-filtrate of Shigella dysenteriae type 1, strain 114Sd was passed over the globotrioside-Fractogel column, and bound toxin eluted with 6 M guanidine-HCl. A yield of 36 mg pure toxin/1 sonicate-filtrate was obtained, i.e. a one step 1224-fold purification. The recovery of biologically active toxin was 87%. The toxin was purified to homogeneity as shown by native PAGE and SDS-PAGE. 相似文献
14.
Jarho EM Venäläinen JI Poutiainen S Leskinen H Vepsäläinen J Christiaans JA Forsberg MM Männistö PT Wallén EA 《Bioorganic & medicinal chemistry》2007,15(5):2024-2031
In order to replace the P2-P1 amide group, different 1-cycloalkenyls and 2-aryls were studied in the place of the P1 pyrrolidine group of a 4-phenylbutanoyl-L-Pro-pyrrolidine structure, which is a well-known prolyl oligopeptidase inhibitor SUAM-1221. The 1-cyclopentenyl and the 2-thienyl groups gave novel compounds, which were equipotent with the corresponding pyrrolidine-analog SUAM-1221. It was shown that the P2-P1 amide group of POP inhibitors can be replaced by an alpha,beta-unsaturated carbonyl group or the aryl conjugated carbonyl group. 相似文献
15.
Photosynthesis of F(1) Hybrids between C(4) and C(3)-C(4) Species of Flaveria 总被引:14,自引:6,他引:8
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Brown RH Bassett CL Cameron RG Evans PT Bouton JH Black CC Sternberg LO Deniro MJ 《Plant physiology》1986,82(1):211-217
Photosynthetic characteristics were studied in several F1 hybrids between C4 and C3-C4 species of Flaveria. Stable carbon isotope ratios, O2 inhibition of apparent photosynthesis, and phosphoenolpyruvate carboxylase activities in the hybrids were similar to the means for the parents. Values of CO2 compensation concentrations were nearer to those of the C4 parent and apparent photosynthesis was below that of both parents, being only 60 and 74% of that of the lowest (C3-C4) parent in two experiments. Reductions of CO2 compensation concentration and O2 inhibition of apparent photosynthesis as well as increases in carbon isotope ratios and phosphoenolpyruvate carboxylase activities compared to values in C3-C4 species suggest transfer of a limited degree of C4 photosynthesis to the F1 hybrids. However, the lower apparent photosynthesis of the hybrids suggests that transfer of C4 characteristics to non-C4 species is detrimental unless characteristics associated with C4 photosynthesis are fully developed. There was a highly significant negative correlation (r = −0.90) between CO2 compensation concentration and the logarithm of phosphoenolpyruvate carboxylase activity in the parents and hybrids, suggesting involvement of this enzyme in controlling the CO2 compensation concentration. Although bundle-sheath cells were more developed in leaves of hybrids than in C3-C4 parents, they appeared to contain lower quantities of organelles than those of the C4 parent. Reduced quantities of organelles in bundle-sheath cells could indicate incomplete compartmentation of partial pathways of the C4 cycle in the hybrids. This may mean that the reduction of CO2 compensation and O2 inhibition of apparent photosynthesis relative to the C3-C4 parents is less dependent on fully developed Kranz anatomy than is increased apparent photosynthesis. 相似文献
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Strappaghetti G Brodi C Giannaccini G Betti L 《Bioorganic & medicinal chemistry letters》2006,16(10):2575-2579
Continuing our research aimed at obtaining new compounds with high affinity and selectivity toward alpha(1)-AR, a new series of arylpiperazine derivatives was designed, synthesized, and biologically tested. The new compounds 1-17 are characterized by a phenylphthalazin-1(2H)-one fragment connected through an alkyl chain to an arylpiperazine residue. The pharmacological profile of these compounds was evaluated for their affinity and selectivity toward alpha(1)-AR, alpha(2)-AR and toward 5HT(1A) serotoninergic receptor. A discussion on the structure-activity relationship (SAR) of these compounds is also reported. 相似文献
18.
Voltage-gated potassium (K(V)) channels can form heteromultimeric complexes with a variety of accessory subunits, including KCNE proteins. Heterologous expression studies have demonstrated diverse functional effects of KCNE subunits on several K(V) channels, including KCNQ1 (K(V)7.1) that, together with KCNE1, generates the slow-delayed rectifier current (I(Ks)) important for cardiac repolarization. In particular, KCNE4 exerts a strong inhibitory effect on KCNQ1 and other K(V) channels, raising the possibility that this accessory subunit is an important potassium current modulator. A polyclonal KCNE4 antibody was developed to determine the human tissue expression pattern and to investigate the biochemical associations of this protein with KCNQ1. We found that KCNE4 is widely and variably expressed in several human tissues, with greatest abundance in brain, liver and testis. In heterologous expression experiments, immunoprecipitation followed by immunoblotting was used to establish that KCNE4 directly associates with KCNQ1, and can co-associate together with KCNE1 in the same KCNQ1 complex to form a 'triple subunit' complex (KCNE1-KCNQ1-KCNE4). We also used cell surface biotinylation to demonstrate that KCNE4 does not impair plasma membrane expression of either KCNQ1 or the triple subunit complex, indicating that biophysical mechanisms probably underlie the inhibitory effects of KCNE4. The observation that multiple KCNE proteins can co-associate with and modulate KCNQ1 channels to produce biochemically diverse channel complexes has important implications for understanding K(V) channel regulation in human physiology. 相似文献
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