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)

Oligodendroglia synthesize myelin in the CNS. In vitro, oligodendroglia may be identified by the binding of monoclonal antibodies against galactocerebroside, a myelin-specific galactolipid. Oligodendroglial trophic factor is a protein mitogen for cells of the oligodendroglial lineage. When oligodendroglia in cerebral white matter cultures are treated with oligodendroglial trophic factor, galactocerebroside-positive cells undergo mitosis but fail to express the myelin structural proteins, myelin basic protein and proteolipid protein. Oligodendroglia treated with oligodendroglial trophic factor, however, do express 2',3'-cyclic nucleotide 3'-phosphodiesterase and myelin-associated glycoprotein in a manner similar to oligodendroglia treated with platelet-derived growth factor. Oligodendroglial trophic factor, therefore, generates a population of somewhat 'immature' oligodendroglia, which are galactocerebroside, myelin-associated glycoprotein and 2', 3'-cyclic nucleotide 3' phosphodiesterase positive but myelin basic protein and proteolipid protein negative.
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PMID:Myelin gene expression in glia treated with oligodendroglial trophic factor. 858 93

This paper describes the purification and properties of a 2',3'-cyclic nucleotide 3'-phosphodiesterase which hydrolyzes nucleoside 2',3'-cyclic monophosphates to nucleoside 2'-phosphates. The enzyme is present in encysted gastrulae of Artemia and its specific activity greatly increases during larval development. The purified enzyme has a molecular weight of around 55 000 as estimated by gel filtration, does not require metals for activity, is inhibited by Zn2+ and inactivated by Cu2+ and has a pH optimum at around neutrality. Based on the relative values of V(max)/Km, the specificity of the phosphodiesterase toward the four 2',3'-cyclic nucleotides is Guo-2',3'-P > Ado-2',3'-P > Cyd-2',3'-P > Urd-2',3'-P = 45:36:20:7. The enzyme from Artemia gastrulae is competitively inhibited by the four nucleosides 2'-phosphates (Ki values around 1 mM) while the enzyme from larvae is only inhibited by the purine nucleotides. The phosphodiesterase characterized in this work is more similar in substrate specificity to the 2',3'-cyclic nucleotide 3'-phosphodiesterase from the mammalian nervous system than to the plant enzyme. The functional relationship of this enzyme with the Artemia ribonuclease VI is discussed.
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PMID:Purification and characterization of Artemia 2',3'-cyclic nucleotide 3'-phosphodiesterase. 864 16

We conditionally immortalized jimpy primary oligodendrocytes (ODCs) with the temperature-sensitive SV40 large T antigen. Two cell lines (clones JP1.1 and JP1.2) were generated that expressed a number of ODC markers. Both jimpy cell lines expressed DM20 mRNAs at the proliferative temperature of 34 degrees C, but not at the "differentiation" temperature of 39 degrees C. Interestingly, at 39 degrees C neither cell line appeared to differentiate further, and neither survived longer than 7 days, in contrast to other ODC cell lines from normal animals that survive many weeks at 39 degrees C. These findings are not consistent with the notion that a PLP/DM20 gene product is the cause of oligodendrocyte cell death in jimpy, since neither jimpy cell line survived at 39 degrees C, and neither line expressed PLP or DM20 proteins. Analysis of the expression of the CNP (2'3' cyclic nucleotide-3'-phosphodiesterase) gene indicated that in both cell lines only one of the two CNP isoforms was expressed at 34 degrees C. Raising the temperature to 39 degrees C caused a greater reduction in the levels of CNP protein than CNP mRNA. Taken together, the DM20 and CNP data suggest that at least some of the decline in myelin/oligodendrocyte components observed in jimpy brains may not be due simply to fewer mature oligodendrocytes, but also to a down regulation of expression of these genes at several levels including transcriptional and post-transcriptional events. Our results provide two cell models for in vitro investigations into the nature of the jimpy mutation at several cellular and molecular levels.
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PMID:Temperature-dependent regulation of PLP/DM20 and CNP gene expression in two conditionally-immortalized jimpy oligodendrocyte cell lines. 913 Feb 45

Multiple sclerosis (MS) is characterized by intra-blood-brain barrier immunoglobulin synthesis that persists lifelong. Subcellular fractionation and two-dimensional electrophoresis were used in conjunction with immune precipitation and immunoblotting to identify antigenic determinants for this immunoglobulin. We report that 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein associated with oligodendrocyte/myelin membranes, also present in lymphocytes and retina, is one major target for the humoral response. Antibodies to CNP are detected in sera of 74% of MS patients. The antibodies are IgM and are present in serum in high titer as well as in cerebrospinal fluid. The antibody response is temporally persistent, consistent with systemic immune activation and persistent antigenic stimulation. Moreover, CNP is isolated as an immune complex from MS brain. CNP is expressed as two isoforms, with CNPII identical to CNPI but with a 20-amino acid extension at the amino terminus of CNPII; however, the antibody response is exclusively restricted to CNPI. In contrast, both isoforms bind the C3 complement, providing a plausible mechanism in MS central nervous system (CNS) for opsonization of myelin membrane CNP, mediated via the C3 receptor, and phagocytosis of CNP-Ig immune complexes, mediated by membrane Ig Fc receptors of macrophages and CNS microglia.
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PMID:Dual implication of 2',3'-cyclic nucleotide 3' phosphodiesterase as major autoantigen and C3 complement-binding protein in the pathogenesis of multiple sclerosis. 957 57

We previously reported cloning of cDNAs encoding both components of a protein doublet induced during goldfish optic nerve regeneration. The predicted protein sequences showed significant homology with the mammalian 2',3'-cyclic-nucleotide 3'-phosphodiesterases (CNPases). CNPases are well-established markers of mammalian myelin; hence, the cDNAs were designated gRICH68 and gRICH70 (for goldfish Regeneration-Induced CNPase Homologues of 68 and 70 kDa). Homologous cDNAs have now been isolated from zebrafish encoding a highly related protein, which we have termed zRICH. RNase protection assays show that zRICH mRNA is induced significantly (fivefold) in optic nerve regenerating zebrafish retinas 7 days following nerve crush. Western blots show a single band in zebrafish brain and retina extracts, with immunoreactivity increasing three-fold in regenerating retinas 21 days postcrush. Immunohistochemical analysis indicated that this increase in zRICH protein expression is localized to the retinal ganglion cell layer in regenerating retina. We have characterized and evaluated the relevance of a conserved beta-ketoacyl synthase motif in zRICH to CNPase activity by means of site-directed mutagenesis. Two residues within the motif, H334 and T336, are critical for enzymatic activity. A cysteine residue within the motif, which corresponds to a critical residue for beta-ketoacyl synthase, does not appear to participate in the phosphodiesterase activity.
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PMID:Cloning and characterization of zRICH, a 2',3'-cyclic-nucleotide 3'-phosphodiesterase induced during zebrafish optic nerve regeneration. 1009 37

The aim of the present study was to assess the sensitivity of central nervous system myelin to acute Pb-toxicity in an animal model, that imitates lead toxicity in occupationally exposed workers, or in occasional incidents of poisoning. Our results indicated that in vivo acute lead intoxication affected both the morphology of myelin and enzymatic activity of the myelin marker, CNPase (2'3'-cyclic nucleotide 3'-phosphodiesterase). The multilayered structure of myelin sheaths was regionally disturbed, with loosely arranged membranes or ovoid-shaped swollen fragments. The activity of CNPase was diminished and Michaelis-Menten kinetics showed a decreased affinity and lower velocity of the enzyme. These data suggest that the disturbances in CNPase activity may contribute, in some extent, to the changes in myelin morphology observed in acute Pb-intoxication.
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PMID:Acute lead intoxication in vivo affects myelin membrane morphology and CNPase activity. 1093 Jan 27

The effects of hypothyroidism on oligodendroglial differentiation and myelination are for the first time studied by immunohistochemical localization of an early oligodendroglial marker, the 2'3'cyclic nucleotide 3'phosphodiesterase (E.C. 3.1.4.37-CNPase), in developing rats. Two groups received methimazol; one during gestation (H) and another postnatally (PN). One H sub-group received thyroxine after birth (T). We observed a delay in CNPase expression followed by a decrease in the number of CNPase immunoreactive fibers in both H and PN groups. The T sub-group was not different from controls. Furthermore, the immunoreactive fibers, in mature hypothyroid animals, showed a continuous pattern of staining in contrast with a discontinuous one in controls. Myelinogenesis is a highly regulated timed event. CNPase links myelin related proteins to the cytoskeleton also interacting with membrane lipids during extension and wrapping of the oligodendroglial process around the axon (ensheathment phase). In mature myelinated fiber the CNPase is absent from compact myelin sheath, being located only in the inner and outer loops and in paranodal loops. Thus, our data suggest a disorder in myelin compaction and point once more to the post-natal period as critical for the mechanisms that are thyroid hormone regulated in myelinogenesis.
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PMID:2'3'Cyclic nucleotide 3'phosphodiesterase immunohistochemistry shows an impairment on myelin compaction in hypothyroid rats. 1115 57

2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP; EC ) catalyzes in vitro hydrolysis of 3'-phosphodiester bonds in 2',3'-cyclic nucleotides to produce 2'-nucleotides exclusively. N-terminal deletion mapping of the C-terminal two-thirds of recombinant rat CNP1 identified a region that possesses the catalytic domain, with further truncations abolishing activity. Proteolysis and kinetic analysis indicated that this domain forms a compact globular structure and contains all of the catalytically essential features. Subsequently, this catalytic fragment of CNP1 (CNP-CF) was used for chemical modification studies to identify amino acid residues essential for activity. 5,5'-Dithiobis-(2-nitrobenzoic acid) modification studies and kinetic analysis of cysteine CNP-CF mutants revealed the nonessential role of cysteines for enzymatic activity. On the other hand, modification studies with diethyl pyrocarbonate indicated that two histidines are essential for CNPase activity. Consequently, the only two conserved histidines, His-230 and His-309, were mutated to phenylalanine and leucine. All four histidine mutants had k(cat) values 1000-fold lower than wild-type CNP-CF, but K(m) values were similar. Circular dichroism studies demonstrated that the low catalytic activities of the histidine mutants were not due to gross changes in secondary structure. Taken together, these results demonstrate that both histidines assume critical roles for catalysis.
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PMID:Identification of essential residues in 2',3'-cyclic nucleotide 3'-phosphodiesterase. Chemical modification and site-directed mutagenesis to investigate the role of cysteine and histidine residues in enzymatic activity. 1127 4

The present study investigated the sensitivity of rats cerebral myelin to prolonged toxicity of lead (Pb) that imitates environmental exposure to this metal. The results indicated that 90 days exposure of young adult rats to lead in drinking water affects the morphology of myelin sheaths, expressed in disintegration of its multilamellar structure. Both, the protein content and the activity of the myelin-specific enzyme CNPase (2',3'-cyclic nucleotide 3-phosphodiesterase), were lowered. The Michaelis-Menten kinetic for CNPase in myelin obtained from control and Pb-treated rats was different. Km increased and Vmax decreased when compared to controls. Observed disturbances in enzyme activity may be one of the potential reasons of the ultrastructural changes. It is thus tempting to speculate that Pb may be considered as a one of the factors contributing to demyelinating diseases.
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PMID:CNPase activity in myelin from adult rat brains after prolonged lead exposure in vivo. 1553 87

Regeneration-induced CNPase homolog (RICH) is an axonal growth-associated protein, which is induced in teleost fish upon optical nerve injury. RICH consists of a highly acidic N-terminal domain, a catalytic domain with 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) activity and a C-terminal isoprenylation site. In vitro RICH and mammalian brain CNPase specifically catalyze the hydrolysis of 2',3'-cyclic nucleotides to produce 2'-nucleotides, but the physiologically relevant in vivo substrate remains unknown. Here, we report the NMR structure of the catalytic domain of goldfish RICH and describe its binding to CNPase inhibitors. The structure consists of a twisted nine-stranded antiparallel beta-sheet surrounded by alpha-helices on both sides. Despite significant local differences mostly arising from a seven-residue insert in the RICH sequence, the active site region is highly similar to that of human CNPase. Likewise, refinement of the catalytic domain of rat CNPase using residual dipolar couplings gave improved agreement with the published crystal structure. NMR titrations of RICH with inhibitors point to a similar catalytic mechanism for RICH and CNPase. The results suggest a functional importance for the evolutionarily conserved phosphodiesterase activity and hint of a link with pre-tRNA splicing.
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PMID:Solution structure of the catalytic domain of RICH protein from goldfish. 1748 Feb 8


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