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 reactivity of recombinant and tumor-derived preparations of oncomodulin toward 5,5'-dithiobis-(2-nitrobenzoate) (Ellman's reagent) and dansylaziridine was investigated. In contrast to previously published data (Mutus, B., Palmer, E. J., and MacManus, J. P. (1988) Biochemistry 27, 5615-5622), the apoprotein was observed to react far more rapidly than the calcium-bound form with Ellman's reagent. Attempts to quantitatively label the native protein with dansylaziridine met with little success, either with the metal-free or calcium-bound forms. In neither case did the extent of modification approach the level observed with the sodium dodecyl sulfate-denatured form of the protein. These results suggest that access to the sulfhydryl group of Cys-18 is severely restricted in the native protein, particularly when the high affinity ion-binding sites are occupied. Consistent with these observations, prolonged incubation of native oncomodulin at room temperature in the absence of reductant did not result in the generation of disulfide-linked dimers, either in the presence or absence of Ca2+. Interestingly, however, Cu2+ ion was observed to facilitate the apparent dimerization of oncomodulin. This reaction, which occurs more rapidly with the Ca2(+)-free form of the protein, affords material with the expected electrophoretic mobility. However, in contrast with the results of Mutus et al., dimeric oncomodulin prepared in this manner fails to stimulate bovine heart cAMP phosphodiesterase.
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PMID:Reactivity of cysteine 18 in oncomodulin. 215 44

Apoprotein E (apo-E) is a surface component of several classes of plasma lipoproteins. It functions as a ligand for receptor-mediated uptake of lipoproteins. Granulosa cells from ovaries of diethylstilbestrol-stimulated hypophysectomized immature rats cultured in serum-free medium with [35S]methionine secretes a 34-kDa protein which reacts with a monospecific anti-rat apo-E antibody and represents 0.2% of total secreted protein. Protease mapping confirms that this protein is apoprotein E. The secreted apoprotein E may be complexed with lipid since it floats in the ultracentrifuge at density less than 1.21 micrograms/ml. Freshly isolated granulosa cells contain receptors for follicle stimulating hormone (FSH) but not for human chorionic gonadotropin (hCG) or prolactin. Apoprotein E secretion is stimulated 2-fold by FSH, but hCG and prolactin have no effect. When granulosa cells develop hCG and prolactin receptors after 48 h of culture with FSH, apoprotein E secretion is not stimulated by addition of FSH, hCG, or prolactin although steroidogenesis is induced. The addition of 10(-7) M androgen plus FSH stimulates a marked increase in progestin synthesis over FSH alone, but androgen has little added effect on apoprotein E secretion. Cholera toxin (1.25 micrograms/ml) and dibutyryl cAMP (5 mg/ml), both of which increase intracellular cAMP, stimulate apo-E secretion 9-fold and 12-fold, respectively. The dibutyryl cAMP effect is dependent on both dose (greater than or equal to 0.5 mg/ml required) and time (onset at 24 h, maximum at 48 h, and back to near baseline at 96 h). Isobutylmethylxanthine, a phosphodiesterase inhibitor, augments FSH-stimulated apoprotein E synthesis 2.5-fold, supporting a role for cAMP in mediating the FSH effect. This is the first demonstration of the hormonal regulation of apoprotein E synthesis in an extrahepatic tissue.
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PMID:Regulation of apolipoprotein E synthesis in rat ovarian granulosa cells. 241 Apr 6

Mouse trophoblast cells are constitutive producers of the thromboplastin apoprotein in vitro. The effects on thromboplastin activity of the three transmethylation inhibitors 3-deazaadenosine (DZA), 3-deazaaristeromycin (DZAri) and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), the four calcium antagonists TMB-8, verapamil, nifedipine and felodipine, the prostaglandin E2 (PGE2), the phosphodiesterase inhibitor 1-methyl 3-isobutylxanthine (MIX) and monensin have been studied. No cytotoxic effects were detected when trypan blue exclusion, release of lactic dehydrogenase, incorporation of 14C-leucine into protein and cell morphology were monitored. TMB-8, felodipine, nifedipine and verapamil all abolished the increase in thromboplastin when added after 68 hr or 90-96 hr in culture. EHNA and DZAri had the same effect (but were only added at 90-96 hr). DZA had a similar effect when added at 68 hr and an even more marked inhibitory effect when added at 90-96 hr. Monensin prevented the increase in thromboplastin activity at 68 hr as well as at 90-96 hr. The combination of DZA and 1-homocysteine thiolactone (Hcy) further increased the inhibition, indicating that in these cases synthesis as well as degradation of thromboplastin were altered. The combination of DZA/Hcy and one of the four calcium antagonists gave no additional inhibitory effect. PGE2 had a biphasic dose-dependent effect. The increased thromboplastin activity at low concentrations of PGE2 (10 ng/ml) was inhibited by addition of one of the compounds verapamil, felodipine, nifedipine or DZA/Hcy. PGE2 at higher levels (10 micrograms/ml) significantly inhibited thromboplastin synthesis. Combination of PGE2 (10 micrograms/ml) and one of the calcium antagonists, DZA/Hcy or MIX gave no significant additive inhibitory effect.
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PMID:Effect of some drugs on thromboplastin activity in mouse trophoblast cells in vitro and in vivo. 242 64

The brain of an 18-year-old patient with Pelizaeus-Merzbacher disease was examined by standard neuropathological and biochemical methods and by immunocytochemical and immunochemical techniques. Analysis revealed a lack of myelin-specific lipids, but showed a residual immunoreactivity for myelin basic protein, myelin-associated glycoprotein, and 2',3'-cyclic nucleotide-3'-phosphodiesterase. Examination by immunocytochemistry and enzyme-linked immunosorbent assay showed an absence of proteolipid apoprotein (lipophilin). The peripheral nervous system was normal. Pelizaeus-Merzbacher disease in humans shares many neuropathological and biochemical features with X-linked mutations in animals, e.g., the jimpy mouse and myelin-deficient rat. The specificity of this protein deficiency in Pelizaeus-Merzbacher disease gains additional support from the recent mapping of the lipophilin gene to the human X chromosome.
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PMID:Defective biosynthesis of proteolipid protein in Pelizaeus-Merzbacher disease. 382 24

Mouse placental cells are probably constitutive producers of the thromboplastin apoprotein in vitro. The effect of cyclic AMP-elevating compounds on their expression of thromboplastin activity has been studied. Dibutyryl cyclic AMP, the phosphodiesterase inhibitor Ro 20-1724 and the adenyl cyclase stimulator forskolin all decrease the synthesis of thromboplastin. Prostaglandin E2 and the phosphodiesterase inhibitor butyl-methyl-xanthine have a biphasic dose dependent effect. A stimulation was observed at low concentrations, whereas higher doses decreased the synthesis of thromboplastin. Adrenaline had no effect. Combination of two compounds, each at maximally inhibiting concentration gave no significant additive inhibitory effect, showing that they probably act via the same pathway.
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PMID:Regulation of thromboplastin synthesis in mouse placental cells in vitro. 619 44

Acyl carrier protein (ACP) functions as a cofactor in fatty acid biosynthesis due to the covalent linkage of an acyl moiety to its 4'-phosphopantetheine prosthetic group. This prosthetic group undergoes turnover in vivo and since the apoprotein is functionally inactive, the interconversion between ACP and apo-ACP has been considered as a possible regulatory point in lipid biosynthesis. To investigate this possibility, the ratio of ACP to apo-ACP was measured in Escherichia coli. An apo-ACP standard was synthesized using [ACP] phosphodiesterase (EC 3.1.4.14) and could be clearly separated from ACP by conformationally sensitive gel electrophoresis, thus providing a reliable assay for the presence of these two species. Antibodies specific for ACP were purified from rabbit serum on an ACP-Sepharose column and subsequently used to synthesize an immunoaffinity column. Chromatography of leucine-labeled cell extracts on this support resulted in the specific binding of ACP, but apo-ACP was not detected in either logarithmically growing or stationary phase cells, although both ACP species bound to the purified anti-ACP IgG. Apo-ACP was not detected as an intermediate in ACP biosynthesis, suggesting that apo-ACP is rapidly converted to ACP following translation. CoA is the biosynthetic precursor to the ACP prosthetic group, but apo-ACP did not accumulate when the intracellular CoA concentration was severely depressed in strain SJ16 (panD), a beta-alanine auxotroph. Strain MP4 (acpS) is conditionally defective in [ACP]synthase (EC 2.7.8.7) and apo-ACP was the predominant form of ACP synthesized in this strain under nonpermissive conditions. Even under conditions that permitted growth, apo-ACP comprised 70% of the total ACP pool in strain MP4. Strain MP4 possessed a phospholipid to protein ratio within the normal range, suggesting that the ratio of ACP to apo-ACP can be significantly altered without affecting total lipid content. Thus, it appears that the prosthetic group turnover cycle maintains all of the ACP in an active form in vivo and a regulatory role for the ACP/apo-ACP ratio seems doubtful.
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PMID:Ratio of active to inactive forms of acyl carrier protein in Escherichia coli. 631 88

Phototropins are a family of plant photoreceptors mediating blue light responses such as phototropism, leaf expansion, chloroplast relocation, and stomatal opening. Characteristic for phototropins are two LOV domains which, when expressed in heterologous systems, each carry a single flavin mononucleotide (FMN) chromophore. Here we describe removal of FMN from the LOV2 domain of Avena sativa using a hydrophobic matrix and successful incorporation of flavin adenine dinucleotide (FAD), riboflavin, and 5'-malonyl-riboflavin into the resulting apoprotein; 5-deaza-FMN was not incorporated under the applied conditions. The chromoproteins reconstituted with the various flavins showed absorption spectra and photocycle almost identical to those of the native LOV2 domain and that reconstituted with FMN except for the kinetics: LOV2-riboflavin and LOV2-5'-malonyl-riboflavin showed more rapid regeneration in the dark. LOV2-FAD can be hydrolyzed to LOV2-FMN with phosphodiesterase, indicating that the adenosine part extrudes from the protein. Together with the data from the X-ray structure (Crosson, S., and Moffat, K. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 2995-3000), the results allow us to decide which of the chromophore-protein interactions are essential for the reconstitution process.
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PMID:Chromophore exchange in the LOV2 domain of the plant photoreceptor phototropin1 from oat. 1572 49

We searched for genes differentially expressed in the frontal cortices of Alzheimer-type dementia (ATD) patients compared with those of non-ATD controls using DNA microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses. Here we show that the expression level of the autotaxin (also called lysophospholipase D or ecto-nucleotide pyrophosphatase/phosphodiesterase 2) gene was significantly greater in ATD cortices than in non-ATD cortices. In both ATD and non-ATD groups, the expression levels were greater in patients with the apoE epsilon3/epsilon4 genotype than in patients with the apoE epsilon3/epsilon3 genotype, although the differences were not statistically significant. These observations suggest that expression of the autotaxin gene and cell signaling by lysophosphatidic acid may be involved in the pathology of ATD, and that this cell signaling pathway may be a potential target of treatments for ATD.
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PMID:Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients. 1652 61

To investigate whether cilostazol (CAS 73963-72-1), a selective phosphodiesterase 3 inhibitor, reduces the progression of atherogenic diet-induced atherosclerosis, cilostazol was orally administered twice a day for 4 weeks to male apolipoprotein-E knockout (ApoE KO) mice. In serial sections of the aortic root, the atherosclerotic lesion ratios in the cilostazol-treated groups (32.5 +/- 3.3% for 100 mg/kg, 29.0 +/- 2.9% for 300 mg/kg) were significantly and dose-dependently smaller than that of the control group (40.2 +/- 3.7%). Cilostazol also significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte/macrophage accumulation in the aortic root and increased high-density lipoprotein(HDL) cholesterol levels in plasma. These results suggest that cilostazol suppresses the progression of atherosclerosis in ApoE KO mice by inhibiting adhesionand infiltration of monocytes and reducing cholesterol accumulation in atherosclerotic lesion.
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PMID:Anti-atherosclerotic effect of cilostazol in apolipoprotein-E knockout mice. 1751 88

Protein crystallography has proven to be an effective method of obtaining high-resolution structures of protein-ligand complexes. However, in certain cases only apoprotein structures are readily available and the generation of crystal complexes is more problematic. Some crystallographic systems are not amenable to soaking of ligands owing to crystal-packing effects and many protein-ligand complexes do not crystallize under the same conditions as used for the apoprotein. Using crystals of human phosphodiesterase 10a (hPDE10a) as an example of such a challenging crystallographic system, the structure of the complex with papaverine was obtained to 2.8 A resolution using protein crystals cross-linked by glutaraldehyde prior to soaking of the ligand. Inspection of the electron-density maps suggested that the correct mode of binding was obtained in one of the two monomers in the asymmetric unit and inspection of crystal-packing contacts explained why cocrystallization experiments and soaking of crystals that were not cross-linked were unsuccessful.
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PMID:Cross-linking of protein crystals as an aid in the generation of binary protein-ligand crystal complexes, exemplified by the human PDE10a-papaverine structure. 1962 71


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