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 role of individual cyclic nucleotide phosphodiesterase (PDE) isozymes in regulating cAMP and cGMP content in intact canine trachealis was examined using isozyme-selective and nonselective PDE inhibitors. The inhibitors used in this study were characterized previously [Mol. Pharmacol. 37:206-214 (1990)] and included: 1) zaprinast, an inhibitor (Ki = 0.1 microM) of the cGMP-specific PDE (cAMP Km = 135 microM; cGMP Km = 4 microM); 2) SK&F 94120, an inhibitor (Ki = 7 microM) of the cGMP-inhibited PDE (cAMP Km = 0.3 microM; cGMP Km = 8 microM); 3) Ro 20-1724, an inhibitor (Ki = 5 microM) of the cAMP-specific PDE (cAMP Km = 4 microM; cGMP Km = 40 microM); and 4) 3-isobutyl-1-methylxanthine (IBMX), a nonselective PDE inhibitor (IC50 = 1-30 microM). In addition to the aforementioned isozymes, canine trachealis contains a Ca2+/calmodulin-stimulated PDE (cAMP Km = 1 microM; cGMP Km = 2 microM) and a GMP-stimulated PDE (cAMP Km = 93 microM; cGMP Km = 60 microM), for which selective inhibitors are not available. Isolated canine trachealis strips were contracted with methacholine and exposed to various concentrations of PDE inhibitors, before being relaxed by the cumulative addition of isoproterenol, an adenylate cyclase activator, or sodium nitroprusside, a guanylate cyclase activator. At the completion of the concentration-response studies, tissues were flash-frozen and assayed for cyclic nucleotide content. Neither isoproterenol-induced relaxation nor cAMP accumulation was altered by zaprinast, but both of these responses were potentiated by pretreatment of tissues with either SK&F 94120 or Ro 20-1724. The effects of SK&F 94120 and Ro 20-1724 were additive, and the combination of SK&F 94120, Ro-1724, and IBMX had no greater effect on the responses to isoproperenol than did either IBMX alone or the combination of SK&F 94120 plus Ro 20-1724. In contrast, zaprinast potentiated sodium nitroprusside-induced relaxation and cGMP accumulation, whereas neither SK&F 94120 nor Ro 20-1724 altered these responses. IBMX produced a greater potentiation than did zaprinast, and the combination of zaprinast and IBMX had a greater effect than either agent alone. The results of this study suggest that the cGMP-inhibited and cAMP-specific PDEs are responsible for cAMP hydrolysis in intact canine trachealis, whereas cGMP hydrolysis is mediated by the cGMP-specific PDE as well as the Ca2+/calmodulin-stimulated PDE and/or the cGMP-stimulated PDE.
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PMID:Role of cyclic nucleotide phosphodiesterase isozymes in intact canine trachealis. 184 59

It is not known whether the enzymes 5'-nucleotide phosphodiesterase/nucleotide pyrophosphatase (EC 3.1.4.1/EC 3.6.1.9) catalyze the transfer of nucleotides to acceptors other than water. We have investigated the action of snake venom and bovine intestinal mucosa phosphodiesterases on nucleoside 5'-polyphosphates in the presence of methanol. In those conditions, GTP was converted by snake venom phosphodiesterase to a mixture of GMP and another compound with a different retention time in reverse-phase high-performance liquid chromatography. That compound, by ultraviolet, 1H- and 13C-nuclear magnetic resonance spectroscopic analysis, and by enzyme analysis, was characterized as the methyl ester of GMP (GMP-OMe). The molar fraction [GMP-OMe]/[GMP + GMP-OMe] formed was higher than the molar fraction of methanol as a solvent in reaction mixtures. Similar reactions took place at comparable rates with snake venom and bovine intestinal mucosa phosphodiesterases using several nucleoside 5'-polyphosphates as substrates. The ability of 5'-nucleotide phosphodiesterases to catalyze transfer reactions to a non-water acceptor is relevant to the mechanism of the enzymes, to their use as analytical tools, and to their possible use/role in the preparative/in vivo synthesis of nucleotide esters.
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PMID:Methanol esterification reactions catalyzed by snake venom and bovine intestinal 5'-nucleotide phosphodiesterases. Formation of nucleoside 5'-monophosphate methyl esters from guanosine 5'-triphosphate and other nucleoside 5'-polyphosphates. 184 20

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

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

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 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 present experiments were performed in anesthetized dogs in order to determine if DN-9693, a new antiplatelet agent known to selectively inhibit cyclic AMP phosphodiesterase (PDE), and isobutylmethylxanthine (IBMX), which inhibits both cyclic AMP and GMP PDEs, have different cardiovascular actions. With intra-arterial administration into the left anterior descending coronary, femoral, cranial mesenteric and renal arterial beds perfused at constant pressure with autologous blood, both agents increased blood flow in a similar dose range. DN-9693 was longer-acting than IBMX. Both agents were nearly equi-effective in the femoral circulation, but DN-9693 was 1.5-2 times less effective than IBMX in the others. With intravenous administration, both agents were equi-effective in increasing the maximum rate of rise of left ventricular pressure heart rate and myocardial oxygen consumption and in reducing mean blood pressure. However, DN-9693 was less effective in increasing coronary sinus outflow than IBMX. These results suggest the following: 1) Vasodilation in the somatic rather than the visceral circulation is important in reducing mean blood pressure. 2) Cyclic GMP may not be involved in the cardiac action of PDE-inhibitors. 3) Cyclic GMP may be involved in the vasodilator effect of PDE-inhibitors in the coronary, mesenteric and renal circulations but least involved in the femoral circulation.
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PMID:Comparison of vasodilator effects of DN-9693, a selective inhibitor of cyclic AMP phosphodiesterase, and isobutylmethylxanthine, a non-selective one, in dogs. 244 35

Nerve growth factor (NGF) rapidly increases the cyclic GMP (cGMP) level about 2-3-fold and enhances the cGMP phosphodiesterase (PDE) activity about 2-fold in rat pheochromocytoma PC12 cells. No changes in the level of cyclic AMP (cAMP) and in the activity of cAMP PDE were found. GTP and a nonhydrolysable analog of GTP, GMP-PCP, at 100 microM, were able to mimic the effect of NGF on the cGMP PDE activity. These results suggest that the cGMP system may be one of the second messengers of NGF action in PC12 cells.
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PMID:Nerve growth factor increases the cyclic GMP level and activates the cyclic GMP phosphodiesterase in PC12 cells. 246 Mar 74

Smooth muscle-mediated expansion and contraction of the vascular sinusoids of the corpora cavernosa may modulate male erectile function. To elucidate the biochemical events that control erection by promoting or inhibiting contraction of cavernosal smooth muscle, tissue from a potent man was grown in cell culture. The cells grew as noncontractile cultures, but had the following smooth muscle cell properties: These cells expressed desmin, the muscle cell-specific intermediate filament protein. They accumulated 45Ca2+ from the medium, which was released by exposure to the ionophore A23187, to cyclic nucleotides (cyclic guanosine 5'-monophosphate [GMP] much greater than cyclic adenosine 3',5'-monophosphate [AMP]), and to the phosphodiesterase inhibitor, papaverine; and; they accumulated Ca2+ in an ATP-dependent manner when the cultured cells were permeabilized by digitonin extraction. ATP-dependent Ca2+ uptake was inhibited approximately 80% by ruthenium red and simulated by cyclic GMP much greater than cyclic AMP. Inositol 1,4,5-trisphosphate (IP3), which is thought to mediate the release of Ca2+ by the smooth muscle cell sarcoplasmic reticulum in vivo, released approximately 0.85 pmol Ca2+/million cells from the digitonin-extracted cells. IP3-dependent release occurred in the presence of ruthenium red and was not affected by cyclic GMP or cyclic AMP. These results indicate that smooth muscle from this human source can be grown successfully in cell culture and that the biochemical pathways that regulate tension in vivo may be perpetuated in vitro. Moreover, some of the clinical responses to drugs administered in situ for erectile dysfunction (e.g. papaverine) may be the result of altered cavernosal smooth muscle cell Ca2+ exchange and may be mediated by cyclic GMP.
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PMID:Characterization of cyclic nucleotide and inositol 1,4,5-trisphosphate-sensitive calcium-exchange activity of smooth muscle cells cultured from the human corpora cavernosa. 246 20


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