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 following evidence suggests that inhibition of hepatoma cell (HTC) growth by cyclic nucleotides is an adenosine-like effect that is greatly modified by the type and treatment of serum used in the culture medium and is probably not mediated by cyclic AMP-dependent protein kinase: 1) Heating serum reduces its phosphodiesterase content, thereby slowing metabolism of cyclic AMP and reducing the inhibition of HTC cell growth by cyclic AMP; 2) Using medium that contains phosphodiesterase but lacks adenosine deaminase causes adenosine to accumulate from cyclic AMP and increases the toxicity of cyclic AMP; 3) Uridine or cytidine reverses the growth inhibition caused by adenosine, 5'-AMP or cyclic AMP; 4) adenosine, 5'-AMP and N6-(delta 2-isopentenyl) adenosine are more toxic for HTC cells than is cyclic AMP, and N6,O2-dibutyryl cyclic AMP is not toxic; and 5) N6,O2'-dibutyryl cyclic AMP inhibits growth of Reuber H35 cells, but uridine prevents this inhibition of growth. We conclude that most, if not all, of the inhibitory effects of cyclic AMP and N6,O2'-dibutyryl cyclic AMP on HTc and Reuber H35 hepatoma cell growth are due to the generation of toxic metabolites.
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PMID:Inhibition of hepatoma cell growth by analogs of adenosine and cyclic AMP and the influence of enzymes in mammalian sera. 612 49

The in vitro effects of cyclic AMP on amino acid transport and synthesis of macromolecules in the Swarm rat chondrosarcoma were investigated using the cyclic AMP analogue, N6-monobutyryl cyclic AMP (MBcAMP), and the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (MIX). Amino acid transport was assessed by measuring alpha-amino-[1-14C]isobutyrate (AIB) uptake. The synthesis of macromolecules was estimated by measuring radiolabeled precursor incorporation into total proteins, proteoglycan, and RNA. MBcAMP stimulated [14C]AIB uptake, [3H]uridine transport, and UTP formation. MBcAMP inhibited 35SO4 and [3H]leucine incorporation into proteoglycan and stimulated [3H]uridine incorporation into RNA. MIX elevated endogenous cyclic AMP levels in the Swarm rat chondrosarcoma and mimicked the effects of MBcAMP on AIB transport and radiolabeled precursor incorporation into macromolecules. For comparative purposes, the effects of MBcAMP on AIB uptake and macromolecule synthesis in rat costal cartilage segments were investigated. MBcAMP and MIX stimulated AIB uptake by costal cartilage segments, inhibited [3H]leucine incorporation into total protein and 35SO4 incorporation into proteoglycan, and had no effect on [3H]uridine incorporation into RNA.
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PMID:Regulation of chondrosarcoma metabolism by cyclic adenosine 3'5'-monophosphate. 615 89

We examined the effects of cyclic AMP (cAMP) on the growth and differentiation of RAO 188 cells, a cultured cell line derived from a retinoblastoma-like tumor induced in an inbred rat by intravitreous inoculation with human adenovirus serotype 12. After adding cAMP analogs (dibutyryl cAMP and 8-bromo cAMP) and phosphodiesterase inhibitors (theophylline, amino-phylline, and 1-methyl-3-isobutyl xanthine) to the RAO 188 cell culture medium, we measured changes in cell incorporation of the DNA and RNA precursors 14C-thymidine and 3H-uridine, and we observed the morphologic alterations of RAO 188 by phase-contrast and transmission and scanning electron microscopy. Incorporation of the labeled precursors decreased with increased concentrations of cAMP analogs and phosphodiesterase inhibitors. Incorporation of the labeled precursors was inhibited shortly after the addition of dibutyryl cAMP to the culture medium. The effect was maximal at 8 hr and was sustained for up to 48 hr. Reversibility of cAMP effects on incorporation gradually decreased for 10 days; at 10 days these effects were essentially irreversible. Neuritelike processes developed shortly after cAMP analog treatment and formed a network after 24 hr. Transmission electron microscopy disclosed changes in the cell membrane and cytoplasm of cells treated with 8-bromo cAMP and theophylline: perturbation of the cell membrane and the appearance of intercellular junctional devices and microfilaments. The activity of glutamate decarboxylase, which is involved in the biosynthesis of gamma-aminobutyric acid, was increased in treated cells. These results show that cAMP decreases DNA and RNA synthesis and cell proliferation and facilitates morphologic and biochemical differentiation of RAO 188 cells.
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PMID:Effects of cyclic AMP on growth and differentiation of rat retinoblastoma-like tumor cells in vitro. 617 45

Purified rat liver nuclei were incubated in vitro in the presence of [adenylate-32P]nicotinamide adenine dinucleotide. The label was rapidly incorporated into trichloroacetic acid-insoluble material and also detected in particles carrying heterogeneous nuclear RNA. The particles were isolated by density gradient centrifugation, and their size determined to be 30-40 S from parallel experiments using nuclei labelled with [3H]uridine 5'-triphosphate under similar conditions. Treatment of the 30-40 S-particles with enzymes of different specificities showed that the label was tightly bound to proteins, not incorporated into nuclei acids and not utilized in phosphorylation of proteins. The label was detached by phosphodiesterase I from snake venom and identified as ADP-ribose and adenosine 5'-phosphate present at a ratio of 7.5 to 1 using thin layer chromatography on poly(ethyleneimine)-cellulose. Radioactively labelled (ADP-ribosylated) proteins were visualized by autoradiography following SDS-polyacrylamide gel electrophoresis. They included several major species of the ribonucleoprotein with molecular weights of 36000, 39000 and 42000, and a limited number of high molecular weight polypeptides.
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PMID:ADP-ribosylation of proteins associated with heterogeneous nuclear RNA in rat liver nuclei. 617 54

In our laboratory, we have studied the mechanism of action of tumor-inhibitory antibiotics, including bleomycin, phleomycin, adriamycin, aclarubicin, neothramycin, macromomycin, auromomycin, chartreusin, pluramycin, neopluramycin, xanthomycin A, angustmycins A and C, blasticidin S and phenomycin. The recent advances are summarized. Screening of microorganism for new antitumor antibiotics based upon our studies on mechanism of action are currently ongoing. We are interested in drug-resistance of tumor cells, and have obtained drug-resistant sublines of murine lymphoblastoma L5178Y cells. We have found that glycoprotein synthesis and alkaline phosphodiesterase (APD) activity of the plasma membrane are higher in adriamycin (ADM)-, aclarubicin (ACR)- and bleomycin (BLM)-resistant cell sublines than in the parental cells. An inhibitor of APD has been isolated from a soil Streptomyces, and identified with 2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone (COTC). COTC inhibits growth of the drug-resistant cells more significantly than the parental cells, and exhibits synergistic activity with ACR against ACR-resistant cells. COTC is a SH inhibitor. Although COTC is a multifunctional drug, the inhibition of DNA polymerase alpha and some mitotic process may be related to its lethal action. In the course of our screening, we have found that a strain of Sterptomyces hygroscopicus produces two substances: one inhibits thymidine and uridine uptake of human leukemic K562 cells, and the other stimulates it. The inhibiting substance has been identified with tubercidin, and the stimulating one has been found to be a novel pyrrolo [2,3-d] pyrimidine antibiotic, cadeguomycin. Cadeguomycin shows low acute toxicity in mice, enhances DTH reaction, and inhibits Ehrlich ascitic carcinoma in mice. The antibiotic exhibits synergistic effects with arabinosylcytosine against growth of K562 cells. Saframycin, discovered by Prof. Arai, Chiba University, is effective against Ehrlich ascitic carcinoma, P388 and L1210 leukemia, and B16 melanoma in mice. The target is DNA. Stubomycin, discovered by Dr. Umezawa, Kitasato Institute, is effective against Sarcoma 180, Ehrlich carcinoma, P388 leukemia, IMC carcinoma and Meth-A tumor in mice, and shows low acute toxicity. The target is plasma membrane.
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PMID:[Study of new antineoplastic antibiotics based on newly discovered action mechanisms]. 619 73

The role of newly synthesized RNA in the differentiation of granulosa cells isolated from diethylstilbestrol-treated immature rats was studied during culture with actinomycin D. Choleragen-induced LH receptor formation and cGMP production at 48 h were completely inhibited by actinomycin D (greater than or equal to 100 ng/ml) added as late as 20 h after the initiation of culture and were partially reduced by addition of the antibiotic from 30-48 h. In contrast, addition of actinomycin D to freshly prepared cells enhanced choleragen-stimulated cAMP accumulation during the 48-h culture period. This effect was caused by both elevation of adenylate cyclase activity at 3 and 6 h of culture and inhibition of choleragen-induced phosphodiesterase activity during culture. The increase in cAMP production by actinomycin D was confined to the first few hours of culture, since the antibiotic did not enhance cAMP levels when added after 3 h and significantly reduced cAMP accumulation when added from 20-48 h of culture. Actinomycin D inhibited choleragen-stimulated incorporation of [3H]uridine into RNA of freshly prepared cells by 65% and reduced both RNA synthesis and incorporation of [3H]leucine into protein at 20 and 48 h of culture by approximately 90%. In untreated cells, RNA and protein synthesis and phosphodiesterase activity increased to a larger extent from 20-48 h than after choleragen treatment, but did not lead to elevated cAMP levels or LH receptors. These results suggest that the cAMP-induced syntheses of RNA and protein that are specific for increases in cGMP production and LH receptor formation occur predominantly during the second day of granulosa cell culture. In contrast, cAMP production can be markedly altered by changes in RNA and protein syntheses during the first hours of culture.
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PMID:Dependence of cyclic nucleotide production and luteinizing hormone receptor formation upon ribonucleic acid synthesis in cultured rat granulosa cells. 620 55

The products derived from the degradation of the sixteen possible diribonucleoside monophosphates (NpN') by Fusarium phosphodiesterase-phosphomonoesterase were analyzed by means of thin layer chromatography. The analysis showed that NpN' was first cleaved into nucleoside N and 5'-nucleotide pN', which was then dephosphorylated to yield nucleoside N'. The dephosphorylation was fast when N' was adenosine or cytidine but slow when N' was guanosine or uridine. The cleavage reaction was followed by measuring the increase of absorbance due to hyperchromicity, and the kinetic constants, Km and kcat, were determined for the sixteen dinucleoside phosphates. The Km value was higher, for a given N, when N' was a pyrimidine nucleoside than when N' was a purine nucleoside. For a given N', uridine as N gave the highest Km value and adenosine gave the lowest one. The kcat value was the highest, for a given N, when N' was cytidine. For a given N', uridine as N gave by far the lowest kcat value. These results can be interpreted in terms of two binding sites on the enzyme with different base preferences. Comparison of kcat/Km values suggested that the base of nucleoside N plays an important role in determining whether a dinucleoside phosphate is a good substrate of the enzyme. The dinucleoside phosphates with uridine as N were found to be particularly poor substrates of the enzyme.
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PMID:Mode of hydrolysis of diribonucleoside monophosphates by phosphodiesterase-phosphomonoesterase of Fusarium moniliforme. 627 68

Cyclic nucleotides phosphodiesterase (PDE) was prepared from cerebrum of male rats and its kinetic properties were studied. The phosphodiesterase preparation exhibited two Michaelis constants, 8.7 microM and 83.3 microM. Adenine derivatives such as adenosine, 5'-AMP and 2'(3')-AMP inhibited the PDE activity at concentrations exceeding 7 X 10(-3)M, and 2'-deoxyadenosine inhibited the activity at lower concentrations (Ki = 1.8 X 10(-3)M); its inhibiting efficacy was almost the same as that of theophylline (Ki = 1.9 X 10(-3)M). Guanine derivatives, on the other hand, showed several different effects. Guanosine and 3',5'-cyclic GMP activated the PDE at 10(-5) M and inhibited at concentrations higher than 10(-4)M. 2'(3')-GMP showed no effect, but 5'-GMP activated markedly at concentrations of 10(-3) to 10(-2)M. Thymidine showed slight inhibitory effect, but cytidine or 2'-deoxycytidine had no effect. Uracil derivatives such as uridine, 5'-UMP, 3',5'-cyclic UMP and 2'(3')-UMP activated the PDE at concentrations exceeding 3 X 10(-3) M. These results indicate that individual nucleosides and nucleotides exhibit structure-activity relationship with PDE.
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PMID:Effects of nucleotides and nucleosides on the activity of cyclic AMP phosphodiesterase from rat brain. 631 97

Pyrimidine nucleosides in blood plasma of rats were identified by different procedures, including chemical peak shift methods, before their quantification by reversed-phase high-performance liquid chromatography. The concentrations of uridine, cytidine, and deoxycytidine were 1.0 +/- 0.2, 10.6 +/- 1.9, and 33.4 +/- 5.4 mumol/l, respectively. Six hours after the administration of D-galactosamine, the level of circulating cytidine was severely depressed to 25% of control values; uridine decreased to 54% while deoxycytidine remained unchanged. 24 h after the dose of the amino sugar, the levels of cytidine and uridine returned to control values in blood plasma. Total acid-soluble uridine, cytidine, guanosine, and adenosine was determined by reversed-phase HPLC after treatment of the neutralized acid-soluble supernatant of freeze-clamped rat livers with phosphodiesterase and alkaline phosphatase. Six hours after its administration, D-galactosamine induced a 2.2-fold and a 1.6-fold rise in total acid-soluble uridine and cytidine, respectively. Co-administration of N-(phosphonoacetyl)-L-aspartate, an inhibitor of de novo pyrimidine synthesis, suppressed the increase in total acid-soluble uridine observed after D-galactosamine alone, but was without effect on the enhancement of total cytidine. Three hours after D-galactosamine and 15 min after [2-14C] cytidine, there was a rapid fall of the labeled nucleoside in blood plasma to 49% of control animals accompanied by a 2.8-fold rise in the total radioactivity of rat liver homogenates. From these results it can be concluded that the hepatocellular rise in total acid-soluble cytidine after D-galactosamine, in contrast to the increase in total acid-soluble uridine, originates from the phosphorylation of blood plasma cytidine via the salvage pathway. The depletion of circulating cytidine in the presence of hepatocellular UTP deficiency points to the importance of the liver and the hepatic UTP level for the clearance of blood plasma cytidine.
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PMID:Depletion of blood plasma cytidine due to increased hepatocellular salvage in D-galactosamine-treated rats. 673 1

A number of the new enzymatically synthesized 2',5'-oligonucleotide trimers, namely, those containing the nucleosides 8-azaadenosine, toyocamycin, sangivamycin, formycin, 8-bromoadenosine, tubercidin, and guanosine, were found to inhibit protein synthesis and cellular proliferation after uptake into intact L and HeLa cells. 2',5'-Oligonucleotide trimers containing cytidine, inosine, uridine, and 1,N6-ethenoadenosine had some effect while those containing 2-chloroadenosine, 3-ribosyladenine, ribavirin, and 2-beta-D-ribofuranosylthiazole-4-carboxamide had no detectable effect on protein synthesis or cellular proliferation after uptake into L or HeLa cells. All of these 2',5'-oligonucleotide analogues inhibited protein synthesis in the in vitro rabbit reticulocyte lysate system except for the trimer containing ribavirin. Such nucleoside substitutions have further defined the substrate-specificity requirements for the endoribonuclease and/or the inhibitors for the 2',5'-phosphodiesterase. Most of the 2',5'-analogues were degraded in L-cell extracts so the endogenous nucleases are not very specific. The 2',5'-trimers containing tubercidin and 2-beta-D-ribofuranosylthiazole-4-carboxamide were quite stable in comparison to the 2',5'-A trimer. The inhibition of protein synthesis and cellular proliferation observed correlated well with the degradation of rRNA and polyadenylated mRNA observed after uptake of the 2',5'-analogues into intact L cells. The degradation of the polyadenylated mRNA appeared to be a more sensitive test than inhibition of cellular protein synthesis for determining biological activities of the 2',5'-oligonucleotide analogues.
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PMID:2',5'-Oligoadenylates and related 2',5'-oligonucleotide analogues. 2. Effect on cellular proliferation, protein synthesis, and endoribonuclease activity. 686 Jun 53


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