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)

Incubation of intact rat fat cells with maximally effective concentrations of insulin (1 nM, 12 min) or isoprenaline (300 nM, 3 min) increased particulate cGMP- and cilostamide-inhibited, low-Km cAMP phosphodiesterase (cAMP-PDE) activity by about 50% and 100%, respectively. In 32P-labeled cells, these agents induced serine 32P-phosphorylation of a 135-kDa particulate protein and, to a variable and lesser extent, a 44-kDa protein, which were selectively immunoprecipitated by anti-cAMP-PDE, as analyzed by SDS/PAGE and autoradiography. In the absence of hormonal stimulation, little phosphorylation was detected (less than 10% of that with the hormones). The two phosphoproteins were identified as cAMP-PDE or a closely related molecule (in the case of the 44-kDa species, perhaps a proteolytic fragment) since (i) amounts of 32P in the immunoprecipitated 135-kDa protein paralleled enzyme inactivation, (ii) prior incubation of the anti-cAMP-PDE with the pure rat or bovine enzyme selectively blocked the immunoprecipitation of the phosphoproteins, (iii) 135- and 44-kDa proteins reacted with the anti-cAMP-PDE on Western immunoblots, and (iv) the two phosphoproteins copurified with cAMP-PDE activity through DEAE-Sephacel chromatography and were isolated by highly selective affinity chromatography on cilostamide-agarose. Thus, in fat cells, catecholamine- and insulin-induced activation of the cAMP-PDE may be mediated via phosphorylation by cAMP-dependent protein kinase and an insulin-activated serine protein kinase, respectively.
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PMID:Evidence that insulin and isoprenaline activate the cGMP-inhibited low-Km cAMP phosphodiesterase in rat fat cells by phosphorylation. 215 56

T and B lymphocyte antigen receptors exhibit single transmembrane spanning regions and very short, three to five amino acid, C-terminal cytoplasmic tails. Ligation of these receptors leads, apparently through GTP binding protein activation, to rapid stimulation of a polyphosphoinositide specific phosphodiesterase (PPI-PDE). T lymphocyte antigen receptors (alpha beta) are coupled to PPI-PDE via a receptor associated complex of membrane proteins, designated CD3. Although an analogous transducer complex is presumed to exist in B cells, no such structure has been defined. We utilized in vitro [32P]phosphorylation to identify and characterize a membrane immunoglobulin (mIg) associated phosphoprotein complex which appears to represent a B cell analog of CD3. The phosphoprotein complex consists of three N-glycosylated polypeptides which occur as disulfide linked dimers, non-covalently associated with mIg. The complex associated with mIgM (pp32, pp34 and pp37 subunits) differs from that associated with mIgD (pp33, pp34 and pp37 subunits), and the isotype specific phosphoprotein (pp32 or pp33) appears to exist as a disulfide linked heterodimer with either pp34 or pp37. Aluminum fluoride stimulates phosphorylation of all of the subunits, and at least one of the proteins is phosphorylated on a tyrosine residue(s).
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PMID:B lymphocyte antigen receptors (mIg) are non-covalently associated with a disulfide linked, inducibly phosphorylated glycoprotein complex. 215 71

K-259-2 and KS-619-1, novel anionic anthraquinone metabolites isolated from culture broth of microorganisms, inhibited activation of bovine brain phosphodiesterase induced by calmodulin (CaM), sodium oleate, or limited proteolysis with almost equal potency. The inhibition of calmodulin-activated phosphodiesterase (CaM-PDE) by K-259-2 or KS-619-1 was overcome by a higher concentration of CaM. Direct interaction of K-259-2 and KS-619-1 with CaM was confirmed through use of hydrophobic fluorescent probes. Kinetic analysis revealed that the inhibition of the trypsin-activated phosphodiesterase was competitively inhibited by K-259-2 or KS-619-1 with respect to cAMP. Addition of a lower amount of either phosphatidylserine or sodium oleate to the reaction mixture was efficacious in attenuating the inhibition of the CaM-PDE by W-7, chlorpromazine, trifluoperazine, compound 48/80, or R-24571 but, in contrast, had little or no effect on the inhibition by K-259-2 or KS-619-1. In conclusion, K-259-2 and KS-619-1, unlike so-called CaM antagonists, do not interact with phosphatidylserine or sodium oleate and it appears that these novel anthraquinone compounds inhibit the enzyme not only via CaM antagonism but possibly also by interacting directly with the enzyme.
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PMID:Inhibition by new anthraquinone compounds, K-259-2 and KS-619-1, of calmodulin-dependent cyclic nucleotide phosphodiesterase. 215 16

cAMP phosphodiesterase was partially purified from pig liver nuclei and some of its properties were investigated. The enzyme is a low km PDE. Inhibition by xanthine derivatives is in line with the behaviour of PDE from other mammalian sources, while small differences are observed towards nucleotides inhibitors. The enzyme is a chromatin-bound protein although no specific location related to transcriptional function could be demonstrated.
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PMID:3'-5' cAMP phosphodiesterase in pig liver nuclei. 215 81

Cyclic GMP-phosphodiesterase (cGMP-PDE) plays a key role in the normal functioning of retinal rod photoreceptor cells. The enzyme is composed of alpha- and beta-catalytic subunits which are inhibited by two identical gamma-subunits. A cDNA encoding the gamma-subunits (PDE gamma) from human retina has been cloned and sequenced. The 1012-bp cDNA has a coding region of 261 bp which is highly homologous to those of the PDE gamma cDNAs from bovine and mouse retinas. Comparison of the deduced amino acid sequences of the proteins from the three species indicates that PDE gamma has been very well conserved through evolution. The mRNA encoded by the cloned cDNA is 1.0 kb long, is similar in size to the corresponding mRNAs from mouse, dog and bovine retinas and is not detected in ground squirrel retina. The PDEG gene has been assigned to human chromosome 17, probably in the region q21.1.
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PMID:Isolation and characterization of cDNA encoding the gamma-subunit of cGMP phosphodiesterase in human retina. 216 80

Pretreatment of rat thymic lymphocytes with Concanavalin A induced a very early (30 min) and substantial increase (+90%) of the soluble cAMP phosphodiesterase activity. The crude cytosolic phosphodiesterase activity of rat thymocytes could reproducively be resolved by Mono-Q ion exchange high performance liquid chromatography into four separate phosphodiesterase peaks: a cGMP-stimulated, two cAMP-specific Rolipram-sensitive and a cGMP-inhibited cardiotrope-sensitive peaks. Concanavalin A stimulated very specifically the activity of the two predominant cAMP-specific Rolipram sensitive peaks whereas it only slightly modified the cGMP-stimulated and the cGMP-inhibited forms. The present results strongly suggest that the Rolipram-sensitive cAMP PDE activity may play a key role in the control and regulation of mitogen-induced thymocyte proliferation.
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PMID:Concanavalin A stimulates the Rolipram-sensitive isoforms of cyclic nucleotide phosphodiesterase in rat thymic lymphocytes. 216 36

In a strain of mice called DI +/+ Severe, nephrogenic (or vasopressin-resistant) diabetes insipidus is caused by an inability of the antidiuretic hormone (ADH, or vasopressin) to increase the water permeability of the renal collecting system. That inability, in turn, arises from abnormally high activity of the enzyme cAMP-phosphodiesterase, specifically of the isozyme type III (PDE-III), which hydrolyzes cAMP and prevents the intracellular buildup of this second messenger. Two rather specific inhibitors of PDE-III, rolipram and cilostamide, used either in vitro or in vivo, reverse the deficiencies in DI +/+ Severe mice by increasing intracellular cAMP and water permeability toward or to their normal values. These results have implications for the treatment of nephrogenic diabetes insipidus in human patients.
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PMID:Causes of the urinary concentrating defect in mice with nephrogenic diabetes insipidus. 216 65

In the inherited degenerative retinal disease of the rd mouse, rod cGMP levels rise above normal due to depressed cGMP-phosphodiesterase (cGMP-PDE) function a few days before degeneration begins. The subnormal activity of the cGMP-PDE may be due to a lesion in the enzyme itself, or in any of several proteins that regulate it. We have used a bovine cDNA for the alpha-subunit of cGMP-PDE to map its gene Pdea to mouse chromosome 18 at a distance of 21 centimorgans (cM) from the Mbp locus. Since the locus of the rd mutation is on mouse chromosome 5, a defect in the Pdea gene is ruled out as the cause of this inherited retinal degeneration.
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PMID:Genetic mapping demonstrates that the alpha-subunit of retinal cGMP-phosphodiesterase is not the site of the rd mutation. 216 32

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 gamma-subunit of retinal rod-outer-segment phosphodiesterase (PDE-gamma) is a multifunctional protein which interacts directly with both of the catalytic subunits of PDE (PDE alpha/beta) and the alpha-subunit of the retinal G (guanine-nucleotide-binding)-protein transducin alpha (T alpha). We have previously reported that the PDE gamma binds to T alpha at residue nos. 24-45 [Morrison. Rider & Takemoto (1987) FEBS Lett. 222, 266-270]. In vitro this results in inhibition of T alpha GTP/GDP exchange [Morrison, Cunnick, Oppert & Takemoto (1989) J. Biol. Chem. 264, 11671-11681]. We now report that the inhibitory region of PDE gamma for PDE alpha/beta occurs at PDE gamma residues 54-87. This binding results in inhibition of either trypsin-solubilized or membrane-bound PDE alpha/beta. PDE gamma which has been treated with carboxypeptidase Y, removing the C-terminus, does not inhibit PDE alpha/beta, but does inhibit T alpha GTP/GDP exchange. Inhibition by PDE gamma can be removed by T alpha-guanosine 5'-[gamma-thio]triphosphate (GTP[S]) addition to membranes. This results in a displacement of PDE gamma, but not in removal of this subunit from the membrane [Whalen, Bitensky & Takemoto (1990) Biochem. J. 265, 655-658]. These results suggest that low levels of T alpha-GTP[S] can result in displacement of PDE gamma from the membrane in vitro as a GTP[S]-T alpha-PDE gamma complex. Further activation by high levels of T alpha-GTP[S] occurs by displacement of PDE gamma from its inhibitory site on PDE alpha/beta, but not in removal from the membrane.
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PMID:Binding of the gamma-subunit of retinal rod-outer-segment phosphodiesterase with both transducin and the catalytic subunits of phosphodiesterase. 217 4


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