Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An enzyme activity splitting FAD to AMP and riboflavin 4',5'-cyclic phosphate (4',5'-cFMN), with a Km of 6-8 microM, was partially purified from the cytosolic fraction of rat liver homogenates. 4', 5'-cFMN was characterized by enzyme, HPLC, UV-visible and NMR spectroscopic analyses. The data suggest that a novel enzyme, tentatively named FAD-AMP lyase (cyclizing) or FMN cyclase, is involved. Also, 4',5'-cFMN was hydrolysed to 5'-FMN by a rat liver cyclic phosphodiesterase. The results indicate a novel enzymic pathway for flavins in mammals, and support the biological relevance of 4',5'-cFMN, perhaps as a flavocoenzyme or a regulatory signal.
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PMID:Enzymic formation of riboflavin 4',5'-cyclic phosphate from FAD: evidence for a specific low-Km FMN cyclase in rat liver1. 948 Sep 5

The synthesis of four ester derivatives of 7-theophylline-acetic acid and glycols by DCC/DMAP-mediated esterification under mild conditions was studied. The structures of the synthesized compounds were proved by microanalyses, UV-, IR-, and 1H-NMR data. Acute toxicity assessment of the compounds in mice showed that compounds 2a-d are less toxic than aminophylline. It was shown by in vivo experiments that 2a-d had depressive action on CNS (increasing of hexobarbital sleeping time and decreasing of spontaneous locomotor activity), and they did not influence to a statistically significant extent the normal 24 hour diuresis of rats (except 2c). The results of cardiovascular screening in rats show that compounds 2a and 2c decreased the heart rate of rats. A pharmacological study of the in vitro broncholytic effect (IC50 and pD2 values) of the derivatives and aminophylline showed that 2c exhibited good broncholytic effect in vitro especially in acetylcholine and serotonin induced guinea pig tracheal contraction. It was demonstrated that compounds 2b,c exerted a stronger inhibitory effect on the enzymic activity of phosphodiesterase in concentration 2 x 10(-3) M than aminophylline.
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PMID:Synthesis, toxicological, pharmacological assessment, and in vitro bronchodilating activity of some 7-theophyllinylacetyloxyglycols. 984 78

The kinetics of PI-PLCgamma1 toward a water-soluble substrate (inositol 1,2-cyclic phosphate, cIP) and phosphatidylinositol (PI) in detergent mixed micelles were monitored by 31P NMR spectroscopy. That cIP is also a substrate (Km = approximately 15 mM) implies a two-step mechanism (intramolecular phosphotransferase reaction to form cIP followed by cyclic phosphodiesterase activity to form inositol-1-phosphate (I-1-P)). PI is cleaved by PI-PLCgamma1 to form cIP and I-1-P with the enzyme specific activity and ratio of products (cIP/I-1-P) regulated by assay temperature, pH, Ca2+, and other amphiphilic additives. Cleavage of both cIP and PI by the enzyme is optimal at pH 5. The effect of Ca2+ on PI-PLCgamma1 activity is unique compared with other isozymes enzymes: Ca2+ is necessary for the activity and low Ca2+ activates the enzyme; however, high Ca2+ inhibits PI-PLCgamma1 hydrolysis of phosphoinositides (but not cIP) with the extent of inhibition dependent on pH, substrate identity (cIP or PI), substrate presentation (e.g. detergent matrix), and substrate surface concentration. This inhibition of PI-PLCgamma1 by high Ca2+ is proposed to derive from the divalent metal ion-inducing clustering of the PI and reducing its accessibility to the enzyme. Amphiphilic additives such as phosphatidic acid, fatty acid, and sodium dodecylsulfate enhance PI cleavage in micelles at pH 7.5 but not at pH 5.0; they have no effect on cIP hydrolysis at either pH value. These different kinetic patterns are used to propose a model for regulation of the enzyme. A key hypothesis is that there is a pH-dependent conformational change in the enzyme that controls accessibility of the active site to both water-soluble cIP and interfacially organized PI. The low activity enzyme at pH 7.5 can be activated by PA (or phosphorylation by tyrosine kinase). However, this activation requires lipophilic substrate (PI) present because cIP hydrolysis is not enhanced in the presence of PA.
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PMID:Action of phosphatidylinositol-specific phospholipase Cgamma1 on soluble and micellar substrates. Separating effects on catalysis from modulation of the surface. 991 11

Calmodulin is known to bind to various amphipathic helical peptide sequences, and the calmodulin-peptide binding surface has been shown to be remarkably tolerant sterically. D-Amino acid peptides, therefore, represent potential nonhydrolysable intracellular antagonists of calmodulin. In the present study, synthetic combinatorial libraries have been used to develop novel D-amino acid hexapeptide antagonists to calmodulin-regulated phosphodiesterase activity. Five hexapeptides were identified from a library containing over 52 million sequences. These peptides inhibited cell proliferation both in cell culture using normal rat kidney cells and by injection via the femoral vein following partial hepatectomy of rat liver cells. These hexapeptides showed no toxic effect on the cells. Despite their short length, the identified hexapeptides appear to adopt a partial helical conformation similar to other known calmodulin-binding peptides, as shown by CD spectroscopy in the presence of calmodulin and NMR spectroscopy in DMSO. The present peptides are the shortest peptide calmodulin antagonists reported to date showing potential in vivo activity.
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PMID:Novel, potent calmodulin antagonists derived from an all-D hexapeptide combinatorial library that inhibit in vivo cell proliferation: activity and structural characterization. 1078 31

Besides isonicotinic acid analogs of pyridine nucleotides, 24 novel pyridine nucleotide cofactors that have an amino acid residue at the carbonyl carbon of the nicotinamide moiety have been prepared by means of transglycosidation reactions catalyzed by rabbit spleen and guinea pig spleen pyridine nucleotide transglycosidases. Their chemical properties were characterized by means of proton NMR, Fab-mass, and UV spectral measurement and phosphodiesterase digestion. Except for the isonicotinic acid ones, these nicotinoylamino acid analogs were shown to function as substrates for both the hydrolysis and the transglycosidation reactions catalyzed by the mammalian NAD glycohydrolases, though their substrate activities were lower than those with the original pyridine nucleotides (NMN, NAD, and NADP). They were inactive in regard to yeast alcohol dehydrogenase- and Thermoanaerobium brockii alcohol dehydrogenase (NADP dependent)-oxidation.
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PMID:Synthesis of pyridine nucleotide analogs consisting of nicotinoylamino acids by means of transglycosidation reactions catalyzed by mammalian pyridine nucleotide transglycosidases. 1235 75

Pulsed-field gradient (PFG) diffusion NMR spectroscopy studies were conducted with several helix-loop-helix regulatory Ca(2+)-binding proteins to characterize the conformational changes associated with Ca(2+)-saturation and/or binding targets. The calmodulin (CaM) system was used as a basis for evaluation, with similar hydrodynamic radii (R(h)) obtained for apo- and Ca(2+)-CaM, consistent with previously reported R(h) data. In addition, conformational changes associated with CaM binding to target peptides from myosin light chain kinase (MLCK), phosphodiesterase (PDE), and simian immunodeficiency virus (SIV) were accurately determined compared with small-angle X-ray scattering results. Both sets of data demonstrate the well-established collapse of the extended Ca(2+)-CaM molecule into a globular complex upon peptide binding. The R(h) of CaM complexes with target peptides from CaM-dependent protein kinase I (CaMKI) and an N-terminal portion of the SIV peptide (SIV-N), as well as the anticancer drug cisplatin were also determined. The CaMKI complex demonstrates a collapse analogous to that observed for MLCK, PDE, and SIV, while the SIV-N shows only a partial collapse. Interestingly, the covalent CaM-cisplatin complex shows a near complete collapse, not expected from previous studies. The method was extended to related calcium binding proteins to show that the R(h) of calcium and integrin binding protein (CIB), calbrain, and the calcium-binding region from soybean calcium-dependent protein kinase (CDPK) decrease on Ca(2+)-binding to various extents. Heteronuclear NMR spectroscopy suggests that for CIB and calbrain this is likely because of shifting the equilibrium from unfolded to folded conformations, with calbrain forming a dimer structure. These results demonstrate the utility of PFG-diffusion NMR to rapidly and accurately screen for molecular size changes on protein-ligand and protein-protein interactions for this class of proteins.
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PMID:Protein conformational changes studied by diffusion NMR spectroscopy: application to helix-loop-helix calcium binding proteins. 1253 86

Phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus thuringiensis catalyzes the hydrolysis of phosphatidylinositol (PI) in a Ca(2+)-independent two-step mechanism: (i) an intramolecular phosphotransferase reaction to form inositol 1,2-(cyclic)-phosphate (cIP), followed by (ii) a cyclic phosphodiesterase activity that converts cIP to inositol 1-phosphate (I-1-P). Moderate amounts of water-miscible organic solvents have previously been shown to dramatically enhance the cyclic phosphodiesterase activity, that is, hydrolysis of cIP. Cosolvents [isopropanol (iPrOH), dimethylsufoxide (DMSO), and dimethylformamide (DMF)] also enhance the phosphotransferase activity of PI-PLC toward PI initially presented in vesicles, monomers, or micelles. Although these water-miscible organic cosolvents caused large changes in PI particle size and distribution (monitored with pyrene-labeled PI fluorescence, 31P NMR spectroscopy, gel filtration, and electron microscopy) that differed with the activating solvent, the change in PI substrate structure in different cosolvents was not correlated with the enhanced catalytic efficiency of PI-PLC toward its substrates. PI-PLC stability was decreased in water/organic cosolvent mixtures (e.g., the T(m) for PI-PLC thermal denaturation decreased linearly with added iPrOH). However, the addition of myo-inositol, a water-soluble inhibitor of PI-PLC, helped stabilize the protein. At 30% iPrOH and 4 degrees C (well below the T(m) for PI-PLC in the presence of iPrOH), cosolvent-induced changes in protein secondary structure were minimal. iPrOH and diheptanoylphosphatidylcholine, each of which activates PI-PLC for cIP hydrolysis, exhibited a synergistic effect for cIP hydrolysis that was not observed with PI as substrate. This behavior is consistent with a mechanism for cosolvent activation that involves changes in active site polarity along with small conformational changes involving the barrel rim tryptophan side chains that have little effect on protein secondary structure.
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PMID:Water-miscible organic cosolvents enhance phosphatidylinositol-specific phospholipase C phosphotransferase as well as phosphodiesterase activity. 1283 83

2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNP) is an enzyme abundantly present in the central nervous system of mammals and some vertebrates. In vitro, CNP specifically catalyzes the hydrolysis of 2',3'-cyclic nucleotides to produce 2'-nucleotides, but the physiologically relevant in vivo substrate remains obscure. Here, we report the medium resolution NMR structure of the catalytic domain of rat CNP with phosphate bound and describe its binding to CNP inhibitors. The structure has a bilobal arrangement of two modules, each consisting of a four-stranded beta-sheet and two alpha-helices. The beta-sheets form a large cavity containing a number of positively charged and aromatic residues. The structure is similar to those of the cyclic phosphodiesterase from Arabidopsis thaliana and the 2'-5' RNA ligase from Thermus thermophilus, placing CNP in the superfamily of 2H phosphodiesterases that contain two tetrapeptide HX(T/S)X motifs. NMR titrations of the CNP catalytic domain with inhibitors and kinetic studies of site-directed mutants reveal a protein conformational change that occurs upon binding.
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PMID:Structural evidence that brain cyclic nucleotide phosphodiesterase is a member of the 2H phosphodiesterase superfamily. 1294 17

A re-investigation of the chemical constituents of the stem bark of Symplocos racemosa Roxb. led to the isolation of four new glycosides, symplocomoside (1), symponoside (2), symplososide (3) and symploveroside (4). Benzoylsalireposide (5) and salireposide (6) were re-isolated from this plant. The structures of the new compounds were determined by 1D and 2D-homonuclear and heteronuclear NMR spectroscopy, chemical evidence, and by comparison with the published data of the closely related compounds. The glycosides 1-4 displayed in vitro inhibitory activity against phosphodiesterase I with IC50 values of 122 +/- 0.017, 698 +/- 0.06, 722 +/- 0.03, 909 +/- 0.09 microM, respectively. The compounds 1-6 also showed in vitro inhibitory activity against thymidine phosphorylase with IC50 values of 189.96 +/- 1.02, 195.56 +/- 2.36, 207.61 +/- 1.06, 488.89 +/- 4.10, 427.20 +/- 5.36, 354.2 +/- 5.69 microM, respectively while 1 was also found to be a urease inhibitor with an IC50 value of 54.13 +/- 0.71 microM.
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PMID:Phosphodiesterase and thymidine phosphorylase-inhibiting salirepin derivatives from Symplocos racemosa. 1564 56

The water residence time and diffusional water permeability in colonic epithelial T84 cancer cells was measured using (1)H NMR spectroscopy; the values estimated were 35.2+/-2.8 ms and (7.4+/-0.6)x10(-3)cms(-1), respectively. Water permeability was inhibited to approximately 10% of its original value by the mercurial diuretic, p-chloromercuribenzenesulfonate (PCMBS; 1mM), and fully restored by dithiothreitol (DTT; 1mM). The permeability was also inhibited reversibly to approximately 55%, by extracellular glibenclamide (1mM), an inhibitor of some ATP-binding cassette (ABC) transporters, including the cystic fibrosis transmembrane conductance regulator (CFTR). Addition of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IMBX; 0.1-1mM) and the adenylate cyclase activator, forskolin (0.1-1mM) did not alter water permeability. It is concluded that in T84 cells water diffuses through the membrane lipid bilayer and via channels that are inhibited by PCMBS, including the channels that are known to be inhibited by glibenclamide.
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PMID:NMR measurements of the diffusional permeability of water in cultured colonic epithelial cancer cells. 1605 61


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