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)

The current model of cellulose biogenesis in plants, as well as bacteria, holds that the membranous cellulose synthase complex polymerizes glucose moieties from UDP-Glc into beta-1,4-glucan chains which give rise to rigid crystalline fibrils upon extrusion at the outer surface of the cell. The distinct arrangement and degree of association of the polymerizing enzyme units presumably govern extracellular chain assembly in addition to the pattern and width of cellulose fibril deposition. Most evident for Acetobacter xylinum, polymerization and assembly appear to be tightly coupled. To date, only bacteria have been effectively studied at the biochemical and genetic levels. In A. xylinum, the cellulose synthase, composed of at least two structurally similar but functionally distinct subunits, is subject to a multicomponent regulatory system. Regulation is based on the novel nucleotide cyclic diguanylic acid, a positive allosteric effector, and the regulatory enzymes maintaining its intracellular turnover: diguanylate cyclase and Ca2(+)-sensitive bis-(3',5')-cyclic diguanylic acid (c-di-GMP) phosphodiesterase. Four genes have been isolated from A. xylinum which constitute the operon for cellulose synthesis. The second gene encodes the catalytic subunit of cellulose synthase; the functions of the other three gene products are still unknown. Exclusively an extracellular product, bacterial cellulose appears to fulfill diverse biological roles within the natural habitat, conferring mechanical, chemical, and physiological protection in A. xylinum and Sarcina ventriculi or facilitating cell adhesion during symbiotic or infectious interactions in Rhizobium and Agrobacterium species. A. xylinum is proving to be most amenable for industrial purposes, allowing the unique features of bacterial cellulose to be exploited for novel product applications.
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PMID:Cellulose biosynthesis and function in bacteria. 203 Jun 72

Visible light changes IR light scatter through a toad retina. This signal presents three components: at low light intensity (100-400 bleached rhodopsins/rod) an early decrease in IR light scatter, of small amplitude, with time to peak of 1-6 s; at intermediate light intensity (1200-16,000 bleached rhodopsins/rod) a slow increase in IR light scatter, with time to peak of 10-30 s; at high light intensity (50,000-160,000 bleached rhodopsins/rod) a last increase in IR light scatter, with time to peak of 1 min. Light sensitivity, amplitude and time to peak of the last two components are increased by inhibitors (3-isobutyl-1-methyl-xanthine and papaverine) of the cyclic 3'5' guanosine monophosphate phosphodiesterase.
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PMID:Light-induced infrared light scattering signal in the retina: effect of phosphodiesterase inhibitors. 212 43

The role of 48-kDa protein in visual transduction remains unresolved. Two hypotheses for its role in quenching the light activation of cyclic GMP cascade suggest that the protein binds to either phosphodiesterase or phosphorylated rhodopsin. Since the protein is also reported to bind ATP, we anticipated that the protein may have ATP hydrolyzing activity, and in analogy with the GTP-binding protein of the rod outer segments, such activity may be greatly enhanced by the elements of transduction cyclic GMP cascade, permitting the protein to function cyclically as GTP-binding protein does. We found that purified 48-kDa protein hydrolyzes ATP but at a slow rate of 0.04-0.05 per min. The Km for ATP is about 45-65 microM. The activity is inhibited noncompetitively by ADP with a Ki of about 50 microM. The ATPase activity of 48-kDa protein is not affected by rhodopsin, bleached rhodopsin, phosphorylated rhodopsin, unactivated cyclic GMP phosphodiesterase, or phosphodiesterase (PDE) activated by GMP PNP-bound G-protein. These data show that although 48-kDa protein has ATPase activity, lack of regulation of this activity by the elements of visual transduction makes it unlikely for this activity to have a role in quenching the light activation of cyclic GMP cascade.
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PMID:Photoreceptor rod outer segment 48-kDa protein has ATPase activity. 215 Jul 55

Two subclasses of cyclic guanosine monophosphate (GMP)-specific phosphodiesterases were identified in vascular tissue from several beds. The activity of one subclass (phosphodiesterase IB) was stimulated severalfold by calmodulin and selectively inhibited by the phosphodiesterase inhibitor TCV-3B. The activity of the other subclass (phosphodiesterase IC) was not stimulated by calmodulin and was selectively inhibited by the phosphodiesterase inhibitor M&B 22,948. To assess the involvement of both subclasses in regulating cyclic GMP-dependent responses, the ability of TCV-3B and M&B 22,948 to potentiate the in vitro and in vivo responses to the endogenous guanylate cyclase stimulator atrial natriuretic factor (ANF) was evaluated. Both TCV-3B and M&B 22,948 relaxed isolated rabbit aortic and pulmonary artery rings and also potentiated the relaxant effect of ANF. In addition, both inhibitors produced small increases in urine flow and sodium excretion in anesthetized rats and potentiated the diuretic and natriuretic responses to exogenous ANF. M&B 22,948 (30 micrograms/kg/min) produced a threefold increase in the natriuretic response to simultaneously administered ANF, and TCV-3B (10 micrograms/kg/min) produced a twofold increase in the response to ANF. The results of the present experiments suggest that both the calmodulin-sensitive and calmodulin-insensitive subclasses of cyclic GMP-specific phosphodiesterase play a role in regulating the in vitro and in vivo response to ANF.
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PMID:Subclasses of cyclic GMP-specific phosphodiesterase and their role in regulating the effects of atrial natriuretic factor. 215 39

Atrial natriuretic factor administered in the large dose did not change glomerular filtration rate, but it was diuretic in low-sodium rats. In response to ANF, excretion of c-GMP was decreased in low-sodium rats in comparison with normal-sodium stimulated c-GMP accumulation in isolated glomeruli was more diminished in low- than normal sodium rats. These results indicate that attenuated glomerular responses to ANF in low-sodium rats might be due to increase of plasma Angiotensin II (Ang II) level, which increases intracellular Ca++ concentration. Theophylline can potentiate the renal response to ANF. We suggest that Ca(++)-activated c-GMP phosphodiesterase plays a major role in the regulation of intracellular accumulation of c-GMP in glomeruli exposed to ANF.
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PMID:Attenuated glomerular responses to atrial natriuretic factor in low-sodium rats is prevented by theophylline. 216 1

An unusual compound, cyclic-bis(3'----5') diguanylic acid (c-di-GMP or cGpGp), is involved in the regulation of cellulose synthesis in the bacterium Acetobacter xylinum. This cyclic dinucleotide acts as an allosteric, positive effector of cellulose synthase activity in vitro (Ka = 0.31 microM) and is inactivated via degradation by a Ca2(+)-sensitive phosphodiesterase, PDE-A (Km = 0.25 microM). A series of 13 analogs cyclic dimer and trimer nucleotides were synthesized, employing a phosphotriester approach, and tested for the ability to mimick c-di-GMP as activators of cellulose synthase and as substrates for PDE-A. Seven of the synthetic compounds stimulate cellulose synthase activity and all of these activators undergo the Ca2(+)-inhibited degradation reaction. The order of affinities for synthase activators is cGpGp approximately cdGpGp approximately cGp(S)Gp (S-diastereomer) greater than cIpGp greater than cdGpdGp greater than cXpGp greater than cIpIp greater than cGp(S)Gp (R-diastereomer). Three cyclic dinucleotides of negligible affinity for either enzyme are cApAp, cUpUp, and cCpCp. This same order of affinities essentially pertains to the analogs as inhibitors of PDE-A activity, but at least one cyclic dinucleotide, cXpXp, which does not bind to cellulose synthase, is also a substrate for the degradation reaction, demonstrating that although the two enzymes share a similar, high degree of specificity for c-di-GMP, their cyclic dinucleotide binding sites are not identical. Phosphodiester bonds of activators in which an exocyclic oxygen is replaced with an atom of sulfur (cGp(S)Gp isomers) resist the action of PDE-A, and such derivatives may be prototypes for synthetic non-hydrolyzable c-di-GMP analogs.
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PMID:The cyclic diguanylic acid regulatory system of cellulose synthesis in Acetobacter xylinum. Chemical synthesis and biological activity of cyclic nucleotide dimer, trimer, and phosphothioate derivatives. 217 38

The fluorescence of 9,10-dioxa-syn-3,4,6,7-tetramethylbimane (bimane) was found to be quenched in the presence of guanosine 5'-monophosphate. By using this phenomenon, the bimane system was used for the fluorophor of substrates for phosphodiesterase I. Bimanes were coupled to 5'-guanylic acid and the resulting compounds were shown to be portent fluorogenic substrates for the assay of phosphodiesterase I.
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PMID:Novel fluorogenic substrates for phosphodiesterase I. 217 81

The first cleavage of embryos derived from random-bred, inbred, and hybrid-inbred female mice was not arrested by purines at concentrations as high as 30 microM. Development after the first or second cleavage was arrested by hypoxanthine, adenosine or inosine, but not guanosine. In agreement with previous results, the purine-induced block was reversed when arrested embryos were transferred to purine-free media after 24 h in culture. The cleavage arrest was not due to elevations of cAMP as a result of inhibition of phosphodiesterase activity since similar concentrations of phosphodiesterase inhibitors or dibutyryl cAMP did not block development. Treatment with inhibitors of enzymes that convert IMP to AMP or to GMP did not reverse the hypoxanthine-induced block, thus demonstrating that mitotic arrest is mediated by a mechanism different from the hypoxanthine arrest of meiosis. Thymidine incorporation studies showed that the block did not prevent the onset of DNA synthesis. The results reveal a profound sensitivity to purine inhibition of a cell process that occurs during the first 30 h of mouse embryo development and is necessary for progession through the G2 or M phases of the second or third cleavage.
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PMID:Purines inhibit the development of mouse embryos in vitro. 225 Feb 45

The purpose of this study was to investigate the relationship between sodium nitroprusside-induced relaxation, inhibition of the sodium-potassium pump, and cyclic guanosine monophosphate. Exposure of rat thoracic aorta to ouabain, or potassium- or magnesium-free Krebs-Ringer bicarbonate solution, procedures which presumably inhibit the sodium-potassium pump, or to potassium chloride or tetraethylammonium, membrane-depolarizing agents, inhibited relaxation to nitroprusside. These conditions had little or no effect on the elevated cyclic guanosine monophosphate levels at a concentration of nitroprusside (0.1 microM) that relaxed norepinephrine contracted tissues by 80%. However, at a maximum relaxant concentration of nitroprusside (1.0 microM), these conditions decreased the elevation of cyclic guanosine monophosphate. The inhibition of elevated cyclic guanosine monophosphate levels was independent of the endothelium, extracellular calcium, and the cyclic guanosine monophosphate phosphodiesterase inhibitor, M&B 22,948. The inhibitory effects of ouabain and of potassium- and magnesium-free solution on the increased levels of cyclic guanosine monophosphate caused by 1.0 microM nitroprusside were abolished when tissues were incubated without norepinephrine, or with norepinephrine in the presence of the alpha-adrenergic blocker, phentolamine. In contrast, a beta-adrenergic blocker, propranolol, had no effect on the ouabain-induced inhibition of elevated cyclic guanosine monophosphate levels, with norepinephrine present. These results are consistent with the hypothesis that membrane events regulate cyclic guanosine monophosphate synthesis. At nitroprusside concentrations greater than 0.1 microM, the formation of cyclic guanosine monophosphate appears to be coupled to the status of the smooth muscle cell membrane and integrity of the sodium-potassium pump.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of sodium-potassium pump inhibitors and membrane-depolarizing agents on sodium nitroprusside-induced relaxation and cyclic guanosine monophosphate accumulation in rat aorta. 240 79

The adenylate-cyclase activator forskolin, the guanylate-cyclase stimulator sodium nitroprusside, the phosphodiesterase inhibitor Ro 15-2041, different Ca-entry blockers, as well as various vasodilators, and the atrial natriuretic peptide were tested for antiplatelet activity. Thrombin, vasopressin, ADP, arachidonic acid, and the dihydropyridine Ca agonist CGP 28392 were used as platelet activators. The physiological and biochemical parameters of platelet function studied included shape-change reaction, intracellular free-Ca modulation, and cyclic nucleotide formation. When inhibition of the shape-change response occurred, it was accompanied by inhibition of the increase in intracellular free Ca. Furthermore, the results suggest a possible intracellular site of action of Ca entry blockers in platelets, and confirm the importance of modulation of cyclic nucleotides in the regulation of platelet function, regardless of the mechanism of platelet activation. Additional antiplatelet activity of antihypertensive agents may have a beneficial effect in reducing the associated risk of thrombo-embolic complications in essential hypertension.
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PMID:Vasodilating agents and platelet function: intracellular free calcium concentration, cyclic nucleotides, and shape-change response. 243 9


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