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)

Papaverine, despite being a potent phosphodiesterase inhibitor, actually blocks adipocyte lipolysis. The present study was designed to clarify the mechanism of the inhibitory effect of papaverine on lipolysis. Lipolysis, stimulated by either 10 microM isoproterenol or 5 mM dibutyryl cAMP, was significantly inhibited by papaverine (100 microM and above). Papaverine, however, did not affect the isoproterenol-induced increase in the protein kinase A (A-kinase) activity ratio. In cell-free extract from non-stimulated adipocytes, cAMP-stimulated A-kinase activities were almost completely blocked by H-89, a potent inhibitor of A-kinase, but not by papaverine. Thus, the inhibitory effect of papaverine on lipolysis could be responsible for a deficit in step(s) distal to A-kinase activity. Hormone-sensitive lipase activities in the infranatant fraction of centrifuged homogenates of cells, which were maximally stimulated with isoproterenol were significantly reduced. This result indicates that hormone-sensitive lipase redistributes from cytosol to its substrate in lipolytically stimulated cells. Papaverine completely blocked the isoproterenol-induced decrease in lipase activity in the infranatant fraction. These results suggest that papaverine blocks lipolysis through its inhibitory effect on the redistribution of hormone-sensitive lipase.
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PMID:Inhibition of adipocyte lipolysis by papaverine: papaverine can inhibit the redistribution of hormone-sensitive lipase. 1089 95

Genistein is a phytoestrogen found in several plants eaten by humans and food-producing animals and exerting a wide spectrum of biological activity. In this experiment, the impact of genistein on lipogenesis and lipolysis was studied in isolated rat adipocytes. Incubation of the cells (10(6) cells/ml in plastic tubes at 37 degrees C with Krebs-Ringer buffer, 90 min) with genistein (0.01, 0.3, 0.6 and 1 mM) clearly restricted (1 nM) [U-14C]glucose conversion to total lipids in the absence and presence of insulin. When [14C]acetate was used as the substrate for lipogenesis, genistein (0.01, 0.1 and 1 mM) exerted a similar effect. Thus, the anti-lipogenetic action of genistein may be an effect not only of alteration in glucose transport and metabolism, but this phytoestrogen can also restrict the fatty acids synthesis and/or their esterification. Incubation of adipocytes with estradiol at the same concentrations also resulted in restriction of lipogenesis, but the effect was less marked. Genistein (0.1 and 1 mM) augmented basal lipolysis in adipocytes. This process was strongly restricted by insulin (1 microM) and H-89 (an inhibitor of protein kinase A; 50 microM) and seems to be primarily due to the inhibitory action of the phytoestrogen on cAMP phosphodiesterase in adipocytes. Genistein at the smallest concentration (0.01 mM) augmented epinephrine-stimulated (1 microM) lipolysis but failed to potentiate lipolysis induced by forskolin (1 microM) or dibutyryl-cAMP (1 mM). These results suggest genistein action on the lipolytic pathways before activation of adenylate cyclase. The restriction of lipolysis stimulated by several lipolytic agents--epinephrine, forskolin and dibutyryl-cAMP were observed when adipocytes were incubated with genistein at highest concentrations (0.1 and 1 mM). These results prove the inhibitory action of this phytoestrogen on the final steps of the lipolytic cascade, i.e. on protein kinase A or hormone sensitive lipase. Estradiol, added to the incubation medium, did not affect lipolysis. It can be concluded that genistein significantly affects lipogenesis and lipolysis in isolated rat adipocytes.
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PMID:Genistein affects lipogenesis and lipolysis in isolated rat adipocytes. 1128 81

The availability of the complete genome sequence of Bacillus subtilis has allowed the prediction of all exported proteins of this Gram-positive eubacterium. Recently, approximately 180 secretory and 114 lipoprotein signal peptides were predicted to direct protein export from the cytoplasm. Whereas most exported proteins appear to use the Sec pathway, 69 of these proteins could potentially use the Tat pathway, as their signal peptides contain RR- or KR-motifs. In the present studies, proteomic techniques were applied to verify how many extracellular B. subtilis proteins follow the Tat pathway. Strikingly, the extracellular accumulation of 13 proteins with potential RR/KR-signal peptides was Tat-independent, showing that their RR/KR-motifs are not recognized by the Tat machinery. In fact, only the phosphodiesterase PhoD was shown to be secreted in a strictly Tat-dependent manner. Sodium azide-inhibition of SecA strongly affected the extracellular appearance of de novo synthesized proteins, including the lipase LipA and two other proteins with predicted RR/KR-signal peptides. The SecA-dependent export of pre-LipA is particularly remarkable, because its RR-signal peptide conforms well to stringent criteria for the prediction of Tat-dependent export in Escherichia coli. Taken together, our observations show that the Tat pathway makes a highly selective contribution to the extracellular proteome of B. subtilis.
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PMID:Selective contribution of the twin-arginine translocation pathway to protein secretion in Bacillus subtilis. 1221 47

Glucose-induced insulin secretion from isolated, perifused rat islets is pulsatile with a period of about 5-10 min, similar to the insulin oscillations that are seen in healthy humans but which are impaired in Type II diabetes. We evaluated the pattern of enhancement by the potent incretin, glucagon-like peptide 1 (GLP-1). GLP-1 increased the amplitude of pulses and the magnitude of insulin secretion from the perifused islets, without affecting the average time interval between pulses. Forskolin and the phosphodiesterase inhibitor isobutylmethylxanthine had the same effect, suggesting that the effect was due to elevated cAMP levels. The possibility that cAMP might enhance the amplitude of pulses by reducing phosphofructo-2-kinase (PFK-2) activity was eliminated when the liver isoform of PFK-2 was shown to be absent from beta-cells. The possibility that cAMP enhanced pulsatile secretion, at least in part, by stimulating lipolysis was supported by the observations that added oleate had a similar effect on secretion, and that the incretin effect of GLP-1 was inhibited by the lipase inhibitor orlistat. These data show that the physiological incretin GLP-1 preserves and enhances normal pulsatile insulin secretion, which may be essential in proposed therapeutic uses of GLP-1 or its analogues.
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PMID:Glucagon-like peptide 1 and fatty acids amplify pulsatile insulin secretion from perifused rat islets. 1235 35

The goal of the present study was to examine cellular mechanisms that regulate adipose cell metabolism in ovariectomized (OVX) and intact rats that were subjected to long-term (27 weeks) treatment with dehydroepiandrosterone (DHEA). Forty-eight 16-month-old female rats were divided into 4 groups of 9 to 11 animals (intact, intact-DHEA, OVX, OVX-DHEA). Adipose tissue lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), and cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (cAMP-PDE) activities were determined, and alpha2-, beta1/beta2-, and beta3-adrenoceptors (ARs) were quantified. DHEA did not affect body weight, fat, or muscle mass in intact rats. The similar retroperitoneal fat pad weight of intact-DHEA rats compared to intact animals was in agreement with the lack of difference in the enzyme activities and AR densities. The increased body weight of OVX rat was paralleled by a greater retroperitoneal adipose tissue mass (P <.01), which was in turn associated with a marked rise in LPL activity (P <.005) and a slight decrease in HSL activity (P <.05) compared to intact animals. OVX-DHEA rats, compared to untreated OVX animals, had a smaller retroperitoneal fat depot, which correlated with a decrease in LPL activity (P <.005) and moderate increase in both HSL activity and beta3-AR density (P <.05). DHEA-treatment lowered fasting insulin and triglyceride levels in both intact and OVX rats (P <.05). Plasma testosterone, androsterone, androstenedione, and androstenediol levels were also significantly increased in both intact-DHEA and OVX-DHEA rats compared to untreated animals (P <.0001). These findings suggest that the antiobesity action of DHEA may be related in part to changes in lipase activities and in beta3-AR density, and that it is dependent on the ovarian status of the animal.
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PMID:Chronic effects of dehydroepiandrosterone on rat adipose tissue metabolism. 1264 61

A study was made of the changes in activity of enzymes involved in the breakdown of stored phytin, lipid, and hemicellulose in the aleurone layer of rice seed (Oryza sativa L., variety IR8) during the 1st week of germination in the light. Enzyme assays were made on crude extracts from degermed seed, and activities were expressed on a per seed basis. Phytase activity increased within the 1st day of germination. The increase in activity of most other enzymes-phosphomonoesterase, phosphodiesterase, esterase, lipase, peroxidase, catalase, beta-glucosidase, and alpha- and beta-galactosidase-closely followed the increase in protein content. Their peak activities occurred by the 5th to the 7th day. Some enzymes, such as beta-1, 3-glucanase and alpha-amylase, continued to increase in activity after the 7th day. Phytase, beta-1, 3-glucanase, and alpha-amylase followed a similar sequence of production in embryoless seed halves incubated in 0.12 muM gibberellin A(3), but the production of lipase was delayed.
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PMID:Changes in the Activity of Some Hydrolases, Peroxidase, and Catalase in the Rice Seed during Germination. 1665 46

Chronic ethanol consumption disrupts G protein-dependent signaling pathways in rat adipocytes. Because lipolysis in adipocytes is regulated by G protein-mediated cAMP signal transduction, we hypothesized that cAMP-regulated lipolysis may be vulnerable to long-term ethanol exposure. Male Wistar rats were fed a liquid diet containing ethanol as 35% of total calories or pair-fed a control diet that isocalorically substituted maltose dextrins for ethanol for 4 wk. Lipolysis was measured by glycerol release over 1 h with or without agonists in adipocytes isolated from epididymal fat. Chronic ethanol feeding decreased beta-adrenergic receptor-stimulated lipolysis, but had no effect on basal lipolysis. In response to beta-adrenergic activation, the early peak of cAMP accumulation was suppressed after ethanol feeding, although the basal cAMP concentration in adipocytes did not differ between pair- and ethanol-fed rats. The suppression in cAMP accumulation caused by ethanol feeding was associated with increased activity of phosphodiesterase 4. Chronic ethanol feeding also decreased beta-adrenergic receptor-stimulated protein kinase A activation and phosphorylation of its downstream proteins, perilipin A and hormone-sensitive lipase, the primary lipase-mediating lipolysis. In conclusion, these data suggest that chronic ethanol feeding increased phosphodiesterase 4 activity in adipocytes, resulting in decreased accumulation of cAMP in response to beta-adrenergic activation and a suppression of beta-adrenergic stimulation of lipolysis.
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PMID:Chronic ethanol feeding suppresses beta-adrenergic receptor-stimulated lipolysis in adipocytes isolated from epididymal fat. 1679 14

N-Acyl ethanolamines (NAEs) are a large class of signaling lipids implicated in diverse physiological processes, including nociception, cognition, anxiety, appetite, and inflammation. It has been proposed that NAEs are biosynthesized from their corresponding N-acyl phosphatidylethanolamines (NAPEs) in a single enzymatic step catalyzed by a phospholipase D (NAPE-PLD). The recent generation of NAPE-PLD(-/-) mice has revealed that these animals possess lower brain levels of saturated NAEs but essentially unchanged concentrations of polyunsaturated NAEs, including the endogenous cannabinoid anandamide. These findings suggest the existence of additional enzymatic routes for the production of NAEs in vivo. Here, we report evidence for an alternative pathway for NAE biosynthesis that proceeds through the serine hydrolase-catalyzed double-deacylation of NAPE to generate glycerophospho-NAE, followed by the phosphodiesterase-mediated cleavage of this intermediate to liberate NAE. Furthermore, we describe the functional proteomic isolation and identification of a heretofore uncharacterized enzyme alpha/beta-hydrolase 4 (Abh4) as a lysophospholipase/phospholipase B that selectively hydrolyzes NAPEs and lysoNAPEs. Abh4 accepts lysoNAPEs bearing both saturated and polyunsaturated N-acyl chains as substrates and displays a distribution that closely mirrors lysoNAPE-lipase activity in mouse tissues. These results support the existence of an NAPE-PLD-independent route for NAE biosynthesis and suggest that Abh4 plays a role in this metabolic pathway by acting as a (lyso)NAPE-selective lipase.
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PMID:Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for alpha/beta-hydrolase 4 in this pathway. 1681 90

A series of novel amphiphilic triblock copolymers of poly(ethyl ethylene phosphate) and poly(-caprolactone) (PEEP-PCL-PEEP) with various PEEP and PCL block lengths were synthesized and characterized. These triblock copolymers formed micelles composed of a hydrophobic core of poly(-caprolactone) (PCL) and a hydrophilic shell of poly(ethyl ethylene phosphate) (PEEP) in aqueous solution. The micelle morphology was spherical, determined by transmission electron microscopy. It was found that the size and critical micelle concentration values of the micelles depended on both hydrophobic PCL block length and PEEP hydrophilic block length. The in vitro degradation characteristics of the triblock copolymers were investigated in micellar form, showing that these copolymers were completely biodegradable under enzymatic catalysis of Pseudomonas lipase and phosphodiesterase I. These triblock copolymers were used for paclitaxel (PTX) encapsulation to demonstrate the potential in drug delivery. PTX was successfully loaded into the micelles, and the in vitro release profile was found to be correlative to the polymer composition. These biodegradable triblock copolymer micelles are potential as novel carriers for hydrophobic drug delivery.
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PMID:Self-assembled micelles of biodegradable triblock copolymers based on poly(ethyl ethylene phosphate) and poly(-caprolactone) as drug carriers. 1808 Dec 52

Lysophosphatidylcholine (LPC) has diverse biological activities through different mechanisms including its conversion into other types of lipid mediators such as lysophosphatidic acid and 2-arachidonoylglycerol. Previously, we found that a large portion of the fluorescent analog of alkyl type LPC (Bodipy-lysoPAF) on porcine kidney epithelial cells (LLC-PK1) was degraded to monoalkylglycerol by lysophospholipase C-like activity and then quickly internalized into the cells. In this study, we investigated whether exogenous fluorescently labeled LPC (NBD-LPC) itself was also metabolized and internalized by a similar mechanism. LLC-PK1 cells converted NBD-LPC to either NBD-MG, possibly due to lysophospholipase C-like activity of ecto-nucleotide pyrophosphatase/phosphodiesterase-6, or to free fatty acid (FA), due to lysophospholipase activity in the culture medium at both sites. The resultant NBD-MG was further degraded to NBD-FA by lipase activity before or after its uptake into the cells, and a portion of NBD-FA was finally released into the culture medium on the opposite side.
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PMID:Ecto-lysophospholipase C controls lysophospholipid uptake and metabolism in porcine kidney epithelial cell line LLC-PK1. 1878 48


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