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)

Analogues of the 2',5'-linked adenylate trimers monophosphate (p5'A2'p5'A2'p5'A) containing 8-hydroxypropyladenosine, 8-bromoadenosine, and 8-hydroxyadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. p5'AHPr2'p5'AHPr2'p5'AHPr (pAHPr3) (1b) and p5'ABr2'p5'ABr2'p5'ABr (pABr3) (1d) were markedly decreased in ability to bind to the 2-5A dependent endonuclease. On the other hand, analogue of the 2',5'-linked adenylate trimer monophosphate substituted by 8-hydroxyadenosine in the first, second, and third nucleotide position was bound about as well as parent 2-5A [pppA(2'p5'A)2] (p3A3) (1e) to RNase L. Additionally, p5'AOH2'p5'AOH2'p5'AOH (pAOH3) (1c) was as active as parent 2-5A in the rRNA cleavage assay, while pAHPr3 (1b) and pABr3 (1d) were devoid of activity. The 8-substituted analogues of 2-5A were more resistant to the degradation by the (2',5') phosphodiesterase. Finally of particular interest was monophosphate, pAOH3 (1c) which possessed nearly 100% of the translation inhibitory activity of 2-5A triphosphate itself. These results suggest that changes in the base-sugar torsion angles of 2-5A may modulate both binding to and activation of mouse L cell RNase L.
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PMID:Purine 8-substitution modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. 202 89

Analogs of 2-5A trimer 5'-monophosphate (2'-5')pA3,p5'A2'p5'A2'p5'A containing 9-(3-fluoro-3-deoxy-c-D-xylofuranosyl)adenine (AF) or 3'-fluoro-3'- deoxyadenosine (AF) at different positions of the chain have been synthesized. All of them were compared with (2'-5')pA3 and (2'-5')pA2 (3'dA) by (i) their ability to bind to 2-5A-dependent endoribonuclease(RNase L) of mouse L cells and of rabbit reticulocyte lysates and (ii) their susceptibility to the degradation by the (2'-5')phosphodiesterase activity. The results of this study suggest that the oligonucleotide conformation is important for its biochemical properties.
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PMID:3'-Fluoro-3'-deoxy analogs of 2-5A 5'-monophosphate: binding to 2-5A-dependent endoribonuclease and susceptibility to (2'-5')phosphodiesterase degradation. 215 12

Effect of (2'-5')oligoadenylate (2-5A) on cellular and viral protein and RNA syntheses was investigated with two mouse cell lines, L929 and Lz (a subclone of L929). The oligonucleotide was introduced into the cells either by using calcium phosphate coprecipitation technique or by microinjection method. In L929 cells protein and viral RNA syntheses were severely inhibited by 2-5A, whereas in Lz cells, both were only slightly inhibited. The activities of 2-5A synthetase and double-stranded (ds)RNA-dependent protein kinase were enhanced by interferon (IFN) treatment roughly to the same extent and there was no significant difference in the level of 2'-5' phosphodiesterase activity either. On the other hand, 2-5A-dependent RNase (RNase L) activity in Lz cells was low, being about 10-20% of that of L929 cells. It was increased twofold after IFN treatment, but protein synthesis of Lz cells was not as sensitive to 2-5A as that of L929 cells even after IFN treatment. L929 and Lz cells were sensitive to the antiviral effect of mouse IFN against vesicular stomatitis virus (VSV) and Mengovirus. In contrast, however, Lz cells were relatively insensitive to the antiviral effect of IFN on vaccinia virus, whereas L929 cells were sensitive.
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PMID:Comparative studies on (2'-5')oligoadenylate-related enzyme systems and the antiviral effect of interferon in two mouse cell lines which differ in (2'-5')oligoadenylate sensitivity of their protein synthesizing system. 241 28

The results of the present study permit the explanation of one of the mechanisms of the interconnection between the regulatory systems of cAMP and 2-5A. cAMP-dependent regulation of 2'-PDE was found to involve phosphorylation of the specific protein inhibitor. Originally, a similar way of regulation of the enzyme activity was discovered for protein phosphatase I. This enzyme has a specific protein inhibitor type 1, which is phosphorylated by cAMP-dependent protein kinase and is activated by phosphorylation (18). It is interesting that the molecular weights of 2'-PDE protein inhibitor and of the inhibitor type 1 of protein phosphatase I are essentially the same. There is also a certain similarity between the above described mechanism and phosphorylation of the regulatory subunit of cAMP-dependent protein kinase type 2. The regulatory subunit can also act as a protein inhibitor of the enzyme and change its properties as a result of phosphorylation (19). The results obtained permit as well a more detailed explanation for cAMP-dependent inhibition of cell proliferation. Evidently, cAMP elevation causes activation of cAMP-dependent phosphorylation which, in turn, leads to the induction of 2-5A synthetase and inhibition of 2'-PDE. As a result of variations in the activities of these enzymes, the level of 2-5A rises. The latter brings about the changes characteristic of the resting state. They involve activation of RNase L and the succeeding acceleration of RNA hydrolysis, inhibition of protein synthesis and cell proliferation. The resting state is characterized by a rapid turnover of macromolecules due to their intensive degradation (20). The above described scheme suggested that the rapid turnover of RNA during inhibition of cell proliferation can be partially accounted for by activation of 2-5A-dependent RNase L. Thus, it can be thought that at least one of the mechanisms of the antiproliferative effect of cAMP-dependent phosphorylation of proteins involves cAMP-dependent elevation of intracellular 2-5A. Evidently, a number of properties of the resting cells are determined by the elevated content of 2-5A. Finally, it should be noted that the interconnection between the systems of cAMP and 2-5A is a multiple process. We have earlier demonstrated (12) that 2-5A activates cAMP phosphodiesterase in NIH 3T3 cell homogenates. These data suggest that the mutual regulation of cAMP and 2-5A levels involves the negative feedback mechanism (Fig. 8).
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PMID:Regulation of 2-5 A phosphodiesterase activity by cAMP-dependent phosphorylation: mechanism and biological role. 300 Jan 46

Molecular hybrids were synthesized by coupling (2'-5')(A)n oligoadenylates or 2-5A, an intracellular mediator involved in antiviral activity of interferons (IFNs), with poly(L-lysine) used as a membrane carrier. (2'-5')(A)n in its free form was not taken up by cells, probably because of its ionic character. Conjugation with the polypeptide carrier overcame this problem and enabled its pharmacological properties to be developed. The alpha-glycol group of individual (2'-5')(A)n oligomers was oxidized by periodate oxidation and conjugated by an amino reductive reaction to poly(L-lysine), Mr 14 000, in a molar ratio of 5:1. These hybrid molecules left the biologically active 5' end moiety of the (2'-5')(A)n molecule unchanged, and in particular its triphosphate group, and stabilized the molecule by increasing its resistance to phosphodiesterase hydrolysis. A dose-dependent inhibition of virus growth was observed on concomitant incubation of (2'-5')(A)n-poly(L-lysine) conjugates with vesicular stomatitis virus infected L1210 cell cultures. This was a result of the activation of the (2'-5')(A)n-dependent endoribonuclease (RNase L) by intracellularly delivered (2'-5')(A)n as in some IFN-treated virus-infected cells. Indeed, (2'-5')(A)n-poly(L-lysine) conjugates bind RNase L effectively as can be seen from their ability to compete with authentic (2'-5')(A)n in a cell-free radiobinding assay. Moreover, (2'-5')(A)n-poly(L-lysine) conjugates promote transient inhibition of protein synthesis and a characteristic cleavage pattern of ribosomal RNAs in intact cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of ribonuclease L by (2'-5')(A)4-poly(L-lysine) conjugates in intact cells. 301 97

To determine whether the 2-5A system has a role in the regulation of cell growth we have examined all constituents of the 2-5A pathway in mouse embryo fibroblasts undergoing one cycle of division at the tertiary stage under conditions where a high degree of uniformity is maintained within each stage of the cycle. Levels of the 2-5A synthetase increased up to tenfold late in S phase and declined as cells moved through G2. A similar but smaller increase in the 2-5A-dependent ribonuclease was observed, whereas activity of the 2'5' phosphodiesterase was highest in quiescent cells. At the time of maximum synthetase levels no phosphorylated 2-5A could be detected in the intact cell. Endogenous interferon (IFN) was found in the culture supernatants in increasing concentration with cell cycle progression and addition of antibodies to IFN reduced the increase in synthetase seen in late S. Treatment of cells with a growth inhibitor that cells produce also affected synthetase activity.
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PMID:Expression of the 2-5A system during the cell cycle. 402 67

To determine the relative importance of the 2',5'-phosphodiester bond of 2-5A in its binding to and activation of the 2-5A-dependent ribonuclease (RNase L, RNase F), a number of phosphodiester linkage isomers of 2-5A were prepared. These isomers were obtained either by lead ion-catalyzed polymerization of adenosine 5'-phosphorimidazolidate or by T4 polynucleotide kinase-catalyzed 5'-phosphorylation of adenylyl(3' leads to 5')adenylyl(3' leads to 5')adenosine followed by reaction of the corresponding phosphorimidazolidates with tri(n-butylammonium)pyrophosphate. The following 2-5A isomers thus were prepared: ppp5'A2'p5'A3'p5'A, ppp5'A3'p5'A2'p5'A, ppp5'A3'p5'A3'p5'A("3-5A"), ppp5'A2'p5'A3'p5'A2'p5'A,and ppp5'A3'p5'A2'p5'-A2'p5'A. The ability of these isomeric 2-5As to interact with the 2-5A-dependent endonuclease was ascertained by three different criteria: (i) ability to prevent the protein synthesis inhibitory effects of 2-5A, (ii) activity as an inhibitor of translation in encephalomyocarditis RNA-programmed L cell extracts, and (iii) ability to prevent binding of the radiolabeled probe, ppp5'A2'p5'A2'p5'A2'p5'A3'[32P]p5'Cp, to the endonuclease of L cell extracts. In certain experiments, degradation of oligonucleotide was minimized or eliminated by altering assay conditions, providing alternate phosphodiesterase substrates, or by using purified endoribonuclease of Ehrlich ascites cells. By all criteria, replacement of 2',5'-bond by a 3',5'-bond led to a substantial decrease in biological activity. Generally, replacement of just one 2',5'-phosphodiester bond with a 3',5'-linkage led to at least a one order of magnitude loss of activity. In accord with this trend, ppp5'A3'p5'A3'p5'A(3-5A) was greater than 10,000 less active than 2-5A in binding to the endonuclease or as an inhibitor of protein synthesis.
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PMID:Biological activities of phosphodiester linkage isomers of 2-5A. 663 Feb 22

A one- and two-dimensional NMR study has been performed on seven A(2'-5')A(2'-5')A fragments containing 9-(3'-fluoro-3'-deoxy-beta-D-xylofuranosyl)-adenine (AF) or 3'-fluoro-3'-deoxyadenosine (AF) residues at different positions, and on the corresponding monomers. A(2'-5')A(2'-5')A served as a reference compound. The fluoro substituent governs the conformation of the sugar ring: an AF residue displays mainly N-type sugar and the ring is considerably flattened (phi N approximately 30 degrees) compared to AF residues (phi S approximately 40 degrees), which exhibit almost pure S-type conformation. Moreover, in AF moieties the rotamer distribution around torsion angle gamma (O5'-C5'-C4'-C3') and the base orientation are influenced to a large extent by the presence of the fluorine substituent. The sugar rings of nonfluorinated residues in the trimers appear rather flexible. A possible correlation between the conformational characteristics of the fluorinated fragments and their biological activity has been found: the fragments that meet the prerequisites for binding to RNase L indeed show enhanced binding to this endonuclease. Furthermore, substitution of the 3'-OH group of the second residue by hydrogen or of the 3'-OH group of the 2'-terminal residue by fluorine or hydrogen results in increased resistance towards 2'-5'-phosphodiesterase.
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PMID:Conformation analysis of 3'-fluorinated A(2'-5')A(2'-5')A fragments. Relation between conformation and biological activity. 817 55

Analogues of the 2',5'-linked adenylate trimer 5'-monophosphates (p5'A2'p5'A2'p5'A) containing 8-hydroxyadenosine and 8-mercaptoadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. The ability of p5'ASH2'p5'ASH2'p5'ASH (pASH3) (1c) to bind 2-5A dependent endonuclease was markedly decreased. On the other hand, an analogue of the 2',5'-linked adenylate trimer monophosphate substituted by 8-hydroxyadenosine in the first, second, and third nucleotide positions bound almost as well as parent 2-5A [pppA(2'p5'A)2] (p3A3) (1d) to RNase L. The 8-substituted analogues of 2-5A were more resistant to the degradation by the (2',5') phosphodiesterase. Of particular interest is monophosphate, pASH3 (1c) which possessed higher anti-HIV activity than pA3 (1a) or pAOH3 (1b).
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PMID:Characterization and biological activity of 8-substituted analogues of 2',5'-oligoadenylates. 846 24

The 2-5A system is an RNA degradation pathway that can be induced by the interferons (IFNs). Treatment of cells with IFN activates genes encoding several double-stranded RNA (dsRNA)-dependent synthetases. These enzymes generate 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A) from ATP. The effects of 2-5A in cells are transient since 2-5A is unstable in cells due to the activities of phosphodiesterase and phosphatase. 2-5A activates the endoribonuclease 2-5A-dependent RNase L, causing degradation of single-stranded RNA with moderate specificity. The human 2-5A-dependent RNase is an 83.5 kDa polypeptide that has little, if any, RNase activity, unless 2-5A is present. 2-5A binding to RNase L switches the enzyme from its off-state to its on-state. At least three 2',5'-linked oligoadenylates and a single 5'-phosphoryl group are required for maximal activation of the RNase. Even though the constitutive presence of 2-5A-dependent RNase is observed in nearly all mammalian cell types, cellular amounts of 2-5A-dependent mRNA and activity can increase after IFN treatment. One well-established role of the 2-5A system is as a host defense against some types of viruses. Since virus infection of cells results in the production and secretion of IFNs, and since dsRNA is both a frequent product of virus infection and an activator of 2-5A synthesis, the replication of encephalomyocarditis virus, which produces dsRNA during its life cycle, is greatly suppressed in IFN-treated cells as a direct result of RNA decay by the activated 2-5A-dependent RNase. This review covers the organic chemistry, enzymology, and molecular biology of 2-5A and its associated enzymes. Additional possible biological roles of the 2-5A system, such as in cell growth and differentiation, human immunodeficiency virus replication, heat shock, atherosclerotic plaque, pathogenesis of Type I diabetes, and apoptosis, are presented.
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PMID:The 2-5A system: modulation of viral and cellular processes through acceleration of RNA degradation. 962 81


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