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)

Mevinolin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, stimulates neurite outgrowth and acetylcholinesterase (ACE) activity in C1300 (Neuro-2A) murine neuroblastoma cells. Sprouting of neurites began within 4-8 h, before changes in cell proliferation could be detected by [3H]thymidine incorporation or flow cytometry. In contrast, the increase in ACE activity was temporally correlated with suppression of DNA synthesis, which occurred after 8 h. The activity of the membrane marker enzyme phosphodiesterase I was not stimulated by mevinolin. Suppression of protein synthesis with cycloheximide blocked the induction of ACE activity but only partially inhibited neurite outgrowth in the mevinolin-treated cultures. When mevinolin was removed from the culture medium, most of the cells retracted their neurites within 2 h, but ACE activity did not decline until DNA synthesis began to return to control levels after 10 h. Similarly, retraction of neurites in differentiated cells exposed to colchicine was not accompanied by a decrease in ACE activity. DNA histograms suggested that mevinolin arrests neuroblastoma cells in both the G1 and G2/M compartments of the cell cycle. Other cytostatic drugs that arrest cells at different stages of the cell cycle did not cause Neuro-2A cells to form neurites such as those seen in the mevinolin-treated cultures. When incorporation of [3H]acetate into isoprenoid compounds was studied in cultures containing mevinolin in concentrations ranging from 0.25 microM to 25 microM, the labeling of cholesterol, dolichol, and ubiquinone was suppressed by 90% or more at all concentrations. However, significant growth arrest and cell differentiation were observed only at the highest concentrations of mevinolin. Supplementing the medium with 100 microM mevalonate prevented the cellular response to mevinolin, but additions of cholesterol, dolichol, ubiquinone, or isopentenyl adenine were generally ineffective. The cholesterol content of neuroblastoma cells incubated with 25 microM mevinolin for 24 h was not diminished, and protein glycosylation, measured by [3H]mannose incorporation, was decreased only after 24 h at high mevinolin concentration. These studies suggest that the stimulation of neurite outgrowth and the increase in ACE activity induced by mevinolin are independent phenomena. Whereas neurite outgrowth is not related directly to the effects of mevinolin on cell cycling, the induction of ACE is correlated with the inhibition of cell proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differentiation of neuroblastoma cells induced by an inhibitor of mevalonate synthesis: relation of neurite outgrowth and acetylcholinesterase activity to changes in cell proliferation and blocked isoprenoid synthesis. 385 9

The location of 2',3'-cyclic nucleotide 2',3'-phosphodiesterase in human erythrocyte membranes was determined. This was accomplished by comparing the enzyme's accessibility with that of glyceraldehyde-3-phosphate dehydrogenase (cytoplasmic surface marker) and acetylcholinesterase (external marker) in sealed and unsealed ghosts and normal and inverted membrane vesicles. The results showed that 2',3'-cyclic nucleotide 3'-phosphodiesterase, like glyceraldehyde-3-phosphate dehydrogenase, meets several criteria for an inner (cytoplasmic) membrane location: (1) the enzyme was accessible to substrate in unsealed ghosts and inside-out vesicles but not in sealed or right-side-out vesicles, (2) latent activity in sealed ghosts could be exposed with detergent (Triton X-100), (3) activity in unsealed ghosts was gradually sequestered during resealing and could be re-exposed with detergent, and (4) the enzyme was susceptible to trypsin proteolysis only in unsealed ghosts. These results demonstrate that the active site of 2',3'-cyclic nucleotide 3'-phosphodiesterase faces the cytoplasm of erythrocytes and that the enzyme may not span the lipid bilayer of the membrane. The localization of the phosphodiesterase on the inner membrane surface of erythrocytes suggests that the similar enzyme of myelin may be embedded within the major dense line of the compact lamellae.
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PMID:Localization of 2',3'-cyclic nucleotide 3'-phosphodiesterase in human erythrocyte membranes. 627 4

Regional distribution of enzymic activities in acetylcholine (ACh) metabolism was examined on thinly-sectioned transverse slices of human spinal cords obtained during autopsy of 5 motor neuron disease (MND) and 5 control patients without MND. Choline acetyltransferase (ChAT) activity was highly concentrated in the ventral horn regions (gray and white matters) of cervical, thoracic and lumbar spinal cord of non-MND patients. This enzyme activity was found to be remarkably low in the ventral gray and white matter of MND patients compared with that of the controls. Although the distribution of acetylcholinesterase (AChE) activity was found to be high in both ventral and dorsal gray matter of the spinal cord, little difference was observed between each corresponding region of MND and control patients, except relatively low enzyme activity in the cervical ventral horn region of MND patients. Muscarinic cholinergic receptors, examined as specific [3H]quinuclidinylbenzilate ([3H]QNB) binding, was also highly concentrated in the ventral and dorsal gray matter of the control spinal cord, and was strongly reduced in the ventral horn region of MND patients, indicating a quite similar distribution pattern of ChAT activity. These biochemical changes of cholinergic transmission system may be paralleled to the morphological degeneration of the spinal lower motor neurons in MND patients. Activity of 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase), a marker enzyme of central myelin structure, was evenly distributed throughout the whole spinal cord section, without regard to the gray and white matter, of both MND and control patients.
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PMID:Regional distribution of cholinergic neurons in human spinal cord transections in the patients with and without motor neuron disease. 628 85

The subcellular localization of calmodulin, cyclic nucleotide phosphodiesterase, and adenylate cyclase was studied in bovine adrenal medulla. Approximately 70% of the calmodulin and 90% of the cAMP phosphodiesterase activities were found colocalized in the cytoplasm. The subcellular distribution of adenylate cyclase closely paralleled the distribution of acetylcholinesterase, a marker for plasma membranes. The fraction of calmodulin which is particulate in nature has a distribution profile very similar to that of adenylate cyclase. The chromaffin granule fraction contained only 0.86% of the total cAMP phosphodiesterase, 0.41% of the total adenylate cyclase, and 1.4% of the total calmodulin.
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PMID:The subcellular localization of calmodulin, cyclic AMP phosphodiesterase, and adenylate cyclase in bovine adrenal medulla. 630 21

Polymorphonuclear leucocytes were isolated from pig blood relatively free from other cells and were characterised biochemically and morphologically and compared with human PMNLs. The activities of 16 enzymes of porcine and human PMNLs were measured and compared. Alkaline phosphatase, acid phosphatase, phosphodiesterase, gamma-glutamyl transpeptidase, NADH-cytochrome c oxidoreductase, malate dehydrogenase and acetylcholinesterase had higher specific activities in procine than in human cells. Alkaline phosphatase has an 87-fold higher specific activity in porcine than in human cells. beta-glucuronidase, lysozyme, beta-galactosidase, N-acetyl-glucosaminidase, beta-glucosidase, myeloperoxidase and catalase had higher specific activities in human than in porcine cells. beta-glucuronidase and myeloperoxidase showed over a 1000- and a 13-fold higher specific activity, respectively, in human than in porcine cells. Porcine PMNLs are readily available in large numbers and are recommended for studies of phagocytosis, chemotaxis and membrane biochemistry.
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PMID:Biochemical characterisation of porcine polymorphonuclear leucocytes: comparison with human polymorphonuclear leucocytes. 687 22

The relationship between adenylate cyclase activity in the synaptic membrane fraction (M1) of rat brain and lipid peroxidation of these membranes was examined. In the presence of 5 mM dithiothreitol (DTT), 1 to 10 microM Fe/+ activated adenylate cyclase 2- to 4-fold. Of several metal ions, Fe2+ was the most effective. Other enzymes in M1, such as Mg2+-ATPase, (Na+-K+)-ATPase, 5'-nucleotidase, acetylcholinesterase, and phosphodiesterase, were not activated by Fe2+ plus DTT. Activation of adenylate cyclase by Fe2+ plus DTT was accompanied by production of malondialdehyde, a product of lipid peroxidation. Formation of malondialdehyde was completely parallel with enzyme activation. Ascorbic acid or a NADPH system also stimulated enzyme activity and caused lipid peroxidation. Activation of the enzyme and lipid peroxidation induced by Fe2+ plus DTT, ascorbic acid, or NADPH was completely prevented by simultaneous addition of N,N'-diphenyl-p-phenylenediamine, an inhibitor of lipid peroxidation. This inhibitor also prevented the decrease in turbidity of the enzyme preparation induced by Fe2+ plus DTT. The stimulatory effects of NaF, guanylyl-5'-imidodiphosphate and calmodulin, respectively, and that of Fe2+ plus DTT on the enzyme activity were additive. Activation of adenylate cyclase by Fe2+ plus DTT was only observed in brain synaptic membranes, not in erythrocyte ghosts, liver plasma membranes, or cardiac sarcolemma. These results indicate that lipid peroxidation of synaptic membranes was accompanied by specific stimulation of adenylate cyclase activity.
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PMID:Activation of adenylate cyclase of rat brain by lipid peroxidation. 721 51

Duvernoy's secretion from representatives of the colubrid genus Boiga has been shown by other workers: (1) to contain an alpha-bungarotoxin-like component (Blanding's tree snake, Boiga blandingi); (2) to exhibit acetylcholine receptor binding activity (the brown tree snake, Boiga irregularis); and (3) to react strongly (B. blandingi and the mangrove snake, Boiga dendrophila) with antisera raised against elapid venoms. The present study provides the first evidence for the presence of acetylcholinesterase, a common elapid enzyme, in the Duvernoy's secretion of B. dendrophila and B. blandingi at levels of 122 +/- 7 and 0.36 +/- 0.02 International Enzyme Units, respectively. Constants for inhibition by eserine were 1.25 x 10(-7) M and 2.79 x 10(-7) M, respectively. The Duvernoy's secretion of B. dendrophila exhibited significant phospholipase and haemolytic activities, whereas phosphodiesterase was only weakly present and no thrombin-like activity was observed.
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PMID:Enzymatic properties of the Duvernoy's secretion of Blanding's tree snake (Boiga blandingi) and of the mangrove snake (Boiga dendrophila). 924 13

Glomeruli at the posterior margin of the main olfactory bulb differ in several respects from those located in the remainder of the bulb; e.g., the olfactory sensory neurons (OSNs) that project here exhibit a distinct biochemical phenotype and signal transduction pathway, the microcircuitry of the glomeruli is substantially altered, and the glomeruli are activated by unconventional odorants. In the present work, we report that the monoclonal antibodies 2C6 and MAb213 label distinct subsets of OSNs in the olfactory epithelium (OE), including their axons to their terminations in the main olfactory bulb (MOB). Neurons immunopositive with 2C6 are concentrated in the cul-de-sacs of ectoturbinates 1 and 2 and of endoturbinate IV. Unlike the vast majority of OSNs, 2C6(+) neurons express olfactory marker protein (OMP) at a low level, but their failure to stain with anti-GAP-43 labeling indicates that the OMP "weak" neurons are nonetheless mature. Glomeruli positive for 2C6 are bilaterally symmetrical and occupy reproducible positions along the posterior margin of the MOB. Three of these are very large, and we refer to them as the lateral, posterior ventral, and anterior ventral 2C6(+) necklace glomeruli. MAb213(+) neurons are concentrated in the posteriormost tips of the cul-de-sacs and recesses at the reflection of the OE at the cribriform plate. Like 2C6(+) neurons, MAb213(+) OSNs are weakly labeled with anti-OMP but are fully mature. MAb213(+) glomeruli are also bilaterally symmetrical; they occupy reproducible positions along the posterior margin of the MOB. The three largest glomeruli occupy lateral, posterior ventral, and posterior positions; the first two are found close to the aforementioned 2C6(+) glomeruli. MAb213 also intensely labels one of the glomeruli of the modified glomerular complex, a string of small glomeruli ventrally, and another string dorsal to the accessory olfactory bulb. Acetylcholinesterase (AChE) histochemical staining of adjacent sections showed that many, but not all, MAb213(+) glomeruli colocalize with dense or moderate AChE staining. Thus, it is likely that the "necklace olfactory glomeruli" (Shinoda et al., 1990, 1993) and the phosphodiesterase (PDE2)(+) glomeruli (Juilfs et al., 1997) are a subset(s) of the MAb213(+) glomeruli. On the other hand, 2C6(+) glomeruli are not associated with AChE staining. These data indicate that the 2C6(+) glomeruli comprise a novel subset in the posterior MOB. In addition to the 2C6(+) and MAb213(+) necklace glomeruli, there is another distinct set of glomeruli at the posterior margin of the bulb that are OMP(-), 2C6(-), and MAb213(-). In summary, the current work indicates that glomeruli at the posterior margin of the bulb, which are necklace glomeruli in terms of location and appearance, are actually heterogeneous and may subserve specialized functions within the olfactory system.
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PMID:Immunohistochemical identification of discrete subsets of rat olfactory neurons and the glomeruli that they innervate. 936 50

R.E. Hill and S.P. Mackessy. Characterization of venom (Duvernoy's secretion) from twelve species of colubrid snakes and partial sequence of four venom proteins. Toxicon XX, xx-yy, 2000. - Venomous colubrids, which include more than 700 snake species worldwide, represent a vast potential source of novel biological compounds. The present study characterized venom (Duvernoy's gland secretion) collected from twelve species of opisthoglyphous (rear-fanged) colubrid snakes, an extremely diverse assemblage of non-venomous to highly venomous snakes. Most venoms displayed proteolytic activity (casein), though activity levels varied considerably. Low phosphodiesterase activity was detected in several venoms (Amphiesma stolata, Diadophis punctatus, Heterodon nasicus kennerlyi, H. n. nasicus and Thamnophis elegans vagrans), and acetylcholinesterase was found in Boiga irregularis saliva and venom, but no venoms displayed hyaluronidase, thrombin-like or kallikrein-like activities. High phospholipase A(2) (PLA(2)) activity was found in Trimorphodon biscutatus lambda venom, and moderate levels were detected in Boiga dendrophila and D. p. regalis venoms as well as B. dendrophila and H. n. nasicus salivas. Non-reducing SDS-PAGE revealed 7-20 protein bands (3.5 to over 200 kD, depending on species) for all venoms analyzed, and electrophoretic profiles of venoms were typically quite distinct from saliva profiles. Components from A. stolata, Hydrodynastes gigas, Tantilla nigriceps and T. e. vagrans venoms showed protease activity when run on gelatin zymogram gels. N-terminal protein sequences for three 26 kD venom components of three species (H. gigas, H. torquata, T. biscutatus) and one 3.5 kD component (T. nigriceps) were also obtained, and the 3.5 kD peptide showed apparent sequence homology with human vascular endothelial growth factor; these data represent the first sequences of colubrid venom components. Protease, phosphodiesterase and PLA(2) activities are also common to elapid and viperid snake venoms, but it is apparent that numerous other (as yet undescribed) components make up the majority of colubrid venom proteins. The complex nature of venoms produced by most species surveyed, and the high levels of protease or phospholipase A(2) activity of some venoms, suggest that many colubrids could become an important source of human health concern as encounters with these snakes increase.
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PMID:Characterization of venom (Duvernoy's secretion) from twelve species of colubrid snakes and partial sequence of four venom proteins. 1085 9

Snake envenomation employs three well integrated strategies: prey immobilization via hypotension, prey immobilization via paralysis, and prey digestion. Purines (adenosine, guanosine and inosine) evidently play a central role in the envenomation strategies of most advanced snakes. Purines constitute the perfect multifunctional toxins, participating simultaneously in all three envenomation strategies. Because they are endogenous regulatory compounds in all vertebrates, it is impossible for any prey organism to develop resistance to them. Purine generation from endogenous precursors in the prey explains the presence of many hitherto unexplained enzyme activities in snake venoms: 5'-nucleotidase, endonucleases (including ribonuclease), phosphodiesterase, ATPase, ADPase, phosphomonoesterase, and NADase. Phospholipases A(2), cytotoxins, myotoxins, and heparinase also participate in purine liberation, in addition to their better known functions. Adenosine contributes to prey immobilization by activation of neuronal adenosine A(1) receptors, suppressing acetylcholine release from motor neurons and excitatory neurotransmitters from central sites. It also exacerbates venom-induced hypotension by activating A(2) receptors in the vasculature. Adenosine and inosine both activate mast cell A(3) receptors, liberating vasoactive substances and increasing vascular permeability. Guanosine probably contributes to hypotension, by augmenting vascular endothelial cGMP levels via an unknown mechanism. Novel functions are suggested for toxins that act upon blood coagulation factors, including nitric oxide production, using the prey's carboxypeptidases. Leucine aminopeptidase may link venom hemorrhagic metalloproteases and endogenous chymotrypsin-like proteases with venom L-amino acid oxidase (LAO), accelerating the latter. The primary function of LAO is probably to promote prey hypotension by activating soluble guanylate cyclase in the presence of superoxide dismutase. LAO's apoptotic activity, too slow to be relevant to prey capture, is undoubtedly secondary and probably serves principally a digestive function. It is concluded that the principal function of L-type Ca(2+) channel antagonists and muscarinic toxins, in Dendroaspis venoms, and acetylcholinesterase in other elapid venoms, is to promote hypotension. Venom dipeptidyl peptidase IV-like enzymes probably also contribute to hypotension by destroying vasoconstrictive peptides such as Peptide YY, neuropeptide Y and substance P. Purines apparently bind to other toxins which then serve as molecular chaperones to deposit the bound purines at specific subsets of purine receptors. The assignment of pharmacological activities such as transient neurotransmitter suppression, histamine release and antinociception, to a variety of proteinaceous toxins, is probably erroneous. Such effects are probably due instead to purines bound to these toxins, and/or to free venom purines.
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PMID:Ophidian envenomation strategies and the role of purines. 1173 31


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