Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.5 (neuropathy target esterase)
 1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal nuclei were isolated from immature rabbit cerebral cortex and nuclear lysophospholipase activities studied using two different 1-acyl lysophospholipids: lysophosphatidylcholine (lysoPC) and lysophosphatidic acid (lysoPA). Our interest in these two lysolipids arose from the observation that lysoPA could promote the acetylation of lysoPC by substantially inhibiting a very active nuclear lysoPC lysophospholipase activity, in a competitive manner (R.R. Baker, H. -y. Chang, Mol. Cell. Biochem. (1999) in press). As there was also evidence for nuclear lysoPA deacylation, it was of interest to see whether one activity could possibly utilize both lysolipid substrates. We now have evidence for two separate lysophospholipase activities in neuronal nuclei. The lysoPC lysophospholipase activity was the more active, more highly enriched in the neuronal nuclei, and showed optimal activity at pH 8.4-9, while the lysoPA lysophospholipase activity was maintained over a much broader pH range. The lysoPC activity was substantially inhibited by free fatty acid, and showed considerable stimulation by serum albumin, while the activity utilizing lysoPA was much less affected by these agents. When lysoPC was added to incubations containing radioactive lysoPA, there was no significant inhibition found in rates of release of radioactive fatty acid, indicating that the lysoPA lysophospholipase activity did not utilize the lysoPC substrate. In incubations with lysoPC, MgATP and CoA brought about a sizable formation of phosphatidylcholine whose radioactivity was equally distributed between the sn-1 and sn-2 positions suggesting labelling both directly from the lysoPC substrate and from fatty acid produced by the lysophospholipase activity. By comparison, with the radioactive lysoPA substrate, MgATP and CoA promoted relatively lower levels of phosphatidic acid formation whose principal labelling came directly from the radioactive lysoPA. Largely because of the high activity of the nuclear lysoPC lysophospholipase, there is considerable potential in the neuronal nucleus to limit the use of lysoPC in other reactions, such as the formation of acylPAF (1-acyl analogue of platelet activating factor). It is of interest that conditions associated with brain ischaemia such as increased free fatty acid levels, falling pH and declines in MgATP may allow a preservation of neuronal nuclear lysoPC levels for acetylation. The existence of a separate lysophospholipase activity for lysoPA allows an independent control of lysoPA which can serve as an important regulator of the nuclear lysoPC lysophospholipase.
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PMID:Evidence for two distinct lysophospholipase activities that degrade lysophosphatidylcholine and lysophosphatidic acid in neuronal nuclei of cerebral cortex. 1032 Aug 8

Neuronal nuclei were isolated from rabbit cerebral cortex, and lipid acetylation reactions were studied because of the high nuclear concentration of acetyltransferases that generate platelet activating factor (PAF) and its acyl analogue AcylPAF. The neuronal nuclear acetylation of 1-palmitoyl lysophosphatidylcholine (lyso PC) was found to be increased more than twofold when low concentrations of lyso PC were incubated in acetylation assays in the presence of 1-palmitoyl lysophosphatidic acid (lyso PA) or 1-hexadecyl glycerophosphate (AGP). This effect was not found for a variety of other acidic and neutral 1-acyl lysoglycerophospholipids. At 4 microM concentrations, AGP was the more effective in increasing rates of lyso PC acetylation, while lyso PA was more effective at 25-35 microM. 1-Stearoyl, 1-alkenyl and 1-decanoyl analogues of lyso PA were all less effective than 1-palmitoyl lyso PA. Phosphatidic acid was considerably less effective than lyso PA, while the acetylated analogue of AGP, AAcGP (alkylacetylglycerophosphate), increased rates of lyso PC acetylation to maxima similar to those seen with lyso PA or AGP. In addition, AAcGP promoted these maxima at considerably lower concentrations (2-4 microM). A mechanism for these effects was suggested when nuclear envelopes (NE), isolated in the presence of PMSF, showed these maximal acetylation rates at low lyso PC concentrations, and these rates were not elevated by the presence of lyso PA. PMSF is a protease inhibitor but can also inhibit lysophospholipase activity. We found a nuclear lysophospholipase that degraded lyso PC at rates more than 13 times those of nuclear lyso PC acetylation. PMSF did inhibit this nuclear lysophospholipase, as did lyso PA, AGP and AAcGP. Kinetic analyses of the effects of lyso PA, AGP and AAcGP on lyso PC lysophospholipase indicated that these three lipids acted as competitive inhibitors for the lyso PC substrate. It is possible that low rates of lyso PC acetylation seen in neuronal nuclei at low lyso PC concentrations, are caused by lyso PC loss mediated by a very strong nuclear lysophospholipase. The effects of lyso PA, AGP and AAcGP in boosting rates of lyso PC acetylation likely come from the inhibition of nuclear lysophospholipase and a preservation of lyso PC concentrations. Competing neuronal nuclear reactions for low endogenous levels of lyso PC may regulate the formation of AcylPAF, and rising lyso PA, AGP or AAcGP concentrations can increase rates of nuclear AcylPAF synthesis.
Mol Cell Biochem 1999 Aug
PMID:Lysophosphatidic acid, alkylglycerophosphate and alkylacetylglycerophosphate increase the neuronal nuclear acetylation of 1-acyl lysophosphatidyl choline by inhibition of lysophospholipase. 1049 77

Organophosphorus pesticide toxicology is normally evaluated in relation to inhibition of cholinesterases (acetyl and butyryl), neuropathy target esterase, and carboxylesterases, with less attention given to other physiologically important hydrolases. This study considers the relative organophosphate sensitivities of the aforementioned serine hydrolases compared with purified blood-clotting factors (thrombin, plasmin, and kallikrein) and digestive enzymes (alpha-chymotrypsin, trypsin, and elastase), assayed under similar conditions. Inhibitors that we examined are organophosphorus insecticides or their activated metabolites (paraoxon, chlorpyrifos oxon, and profenofos) and other toxicants (phenyl saligenin cyclic phosphonate and tribufos) for comparison with values that are found in the literature for the fluorophosphonates (isoflurophate and sarin). Thrombin is the most sensitive blood-clotting factor with IC-50 values of 19 to 160 microM for tribufos, the cyclic phosphonate, isoflurophate, and profenofos; plasmin and kallikrein are less affected (IC-50 >100 microM). Alpha-Chymotrypsin, trypsin, and elastase are most sensitive to the cyclic phosphonate (IC-50 1.3-15 microM) and less so to isoflurophate, sarin, and profenofos (IC-50 values from 3.6 to greater than 100 microM). The cholinesterases, carboxylesterase, and neuropathy target esterase are the most sensitive to inhibition with IC-50 values for the insecticides of less than 0.001 to 0.6, 0.002 to 0.009, and 0.15 to 100 microM, respectively. The generally low potency of these organophosphates for blood-clotting factors and digestive enzymes suggests that associated toxic effects are unlikely at sublethal doses.
J Biochem Mol Toxicol 2000
PMID:Sensitivity of blood-clotting factors and digestive enzymes to inhibition by organophosphorus pesticides. 1056 Oct 82

Neuronal nuclei isolated from rabbit cerebral cortex were found to be enriched in an NEM-insensitive lysophosphatidic acid (lysoPA) phosphohydrolase activity. LysoPA is an inhibitor of the nuclear lysophosphatidylcholine (lysoPC) lysophospholipase, and by preserving lysoPC levels, lysoPA boosted the nuclear production of the acyl analogue of platelet-activating factor by promoting the acetylation of lysoPC (Baker and Chang, Mol. Cell Biochem., 1999, in press). The nuclear phosphohydrolase converts lysoPA to 1-monoacylglycerol, and thus eliminates this lysoPA inhibition of lysoPC lysophospholipase. The nuclear lysoPA phosphohydrolase specific activity was more than three times that observed for the nuclear lysoPA lysophospholipase (Baker and Chang, Biochim. Biophys. Acta 1438 (1999) 253-263) and represents a more active route for nuclear lysoPA removal. The neuronal nuclear lysoPA phosphohydrolase was inhibited at acidic pH, and also inhibited by calcium ions. The 1-monoacylglycerol product of the phosphohydrolase is rapidly degraded by neuronal monoacylglycerol lipase, an enzyme some sevenfold more active than the phosphohydrolase and sensitive to inhibition by arachidonoyl trifluoromethyl ketone (AACOCF(3)). Both acidic pH and free fatty acid inhibited the lipase. In the absence of AACOCF(3), production of fatty acid from lysoPA substrate could be largely attributed to the sequential actions of the nuclear phosphohydrolase and lipase. This facilitates fatty acid recycling back into phospholipid by lysophospholipid acylation when ATP levels are restored following periods of brain ischemia. At relatively low concentrations, sphingosine-1-phosphate, and alkylglycerophosphate were the most effective phosphohydrolase inhibitors while phosphatidic acid, alkylacetylglycerophosphate and ceramide were without effect. LysoPA is an interesting regulatory molecule that can potentially preserve lysophosphatidylcholine within the nuclear membrane for use in acetylation reactions. Thus conditions relevant to brain ischemia such as falling pH, falling ATP concentrations, rising fatty acid and intracellular calcium levels may, by slowing this metabolic path for lysoPA loss, promote the production of acyl PAF and contribute to the increased levels of the acetylated lipids noted in ischemia.
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PMID:A metabolic path for the degradation of lysophosphatidic acid, an inhibitor of lysophosphatidylcholine lysophospholipase, in neuronal nuclei of cerebral cortex. 1060 95

The human pathogenic fungus Cryptococcus neoformans secretes a phospholipase enzyme that demonstrates phospholipase B (PLB), lysophospholipase hydrolase and lysophospholipase transacylase activities. This enzyme has been postulated to be a cryptococcal virulence factor. We cloned a phospholipase-encoding gene (PLB1) from C. neoformans and constructed plb1 mutants using targeted gene disruption. All three enzyme activities were markedly reduced in the mutants compared with the wild-type parent. The plb1 strains did not have any defects in the known cryptococcal virulence phenotypes of growth at 37 degrees C, capsule formation, laccase activity and urease activity. The plb1 strains were reconstituted using the wild-type locus and this resulted in restoration of all extracellular PLB activities. In vivo testing demonstrated that the plb1 strain was significantly less virulent than the control strains in both the mouse inhalational model and the rabbit meningitis model. We also found that the plb1 strain exhibited a growth defect in a macrophage-like cell line. These data demonstrate that secretory phospholipase is a virulence factor for C. neoformans.
Mol Microbiol 2001 Jan
PMID:Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans. 1112 98

CoA-independent transacylase activities generating alkylacylglycerophosphocholine (AAGPC) from alkylglycerophosphocholine (1-alkyl GPC) were considerably enriched in neuronal nuclei isolated from rabbit cerebral cortex. Specific nuclear transacylation activities were 13 times the corresponding microsomal values. Several lysophospholipids, notably 1-acyl glycerophosphocholine (1-acyl GPC), 1-alkenyl GPC and 1-alkenyl GPE (1-alkenyl glycerophosphoethanolamine) inhibited the transacylation of 1-alkyl GPC. The inhibitory effects of 1-acyl GPC were seen in the presence of MAFP (methyl arachidonoylfluorophosphonate) or free oleate, compounds that inhibit neuronal nuclear lysophospholipase. When neuronal nuclei were preincubated with 1-alkyl GPC, the radioactive AAGPC product served as donor in transacylation reactions, to generate 1-alkyl GPC. In these nuclear reactions, 1-palmitoyl GPE and 1-palmitoyl GPC appeared to be poor acceptor substrates, when compared with corresponding 1-alkyl and 1-alkenyl analogues. The presence of free oleate or MAFP in the reactions containing 1-acyl GPC boosted the release of 1-alkyl GPC from AAGPC. These observations are of particular relevance to brain ischemia in which lysophospholipid, free fatty acid, and platelet-activating factor (PAF) levels rise dramatically. PAF can be made by the nuclear acetylation of 1-alkyl GPC, which is formed by nuclear transacylation mechanisms. Yet transacylase also removes 1-alkyl GPC, and thus this enzyme activity can regulate 1-alkyl GPC availability. Our observations indicate that lysophospholipids promote the formation of 1-alkyl GPC from nuclear AAGPC via transacylation, while free fatty acid likely prolongs the lifetime of 1-acyl lysophospholipids substrates by lysophospholipase inhibition. Similarly, once 1-alkyl GPC is formed, other lysophospholipids effectively compete with this 1-alkyl analogue and reduce its conversion back to AAGPC by transacylation. Free oleate, in this case, sustains 1-acyl lysophospholipid inhibitors of 1-alkyl GPC transacylation. Thus the cycle of transacylation may favour 1-alkyl GPC formation during ischemia, increasing levels of 1-alkyl GPC for nuclear acetylation reactions and PAF formation. The nuclear generation of PAF is of considerable importance as PAF can play regulatory roles in transcription events associated with inflammation.
Mol Cell Biochem 2000 Dec
PMID:The regulation of CoA-independent transacylation reactions in neuronal nuclei by lysophospholipid, free fatty acid, and lysophospholipase: the control of nuclear lyso platelet-activating factor metabolism. 1120 49

The group VIA PLA2 is a member of the PLA2 superfamily. This enzyme, which is cytosolic and Ca2+-independent, has been designated iPLA2beta to distinguish it from another recently cloned Ca2+-independent PLA2. Features of iPLA2beta molecular structure offer some insight into possible cellular functions of the enzyme. At least two catalytically active iPLA2beta isoforms and additionalsplicing variants are derived from a single gene that consists of at least 17 exons located on human chromosome 22q13.1. Potential tumor suppressor genes also reside at or near this locus. Structural analyses reveal that iPLA2beta contains unique structural features that include a serine lipase consensus motif (GXSXG), a putative ATP-binding domain, an ankyrin-repeat domain, a caspase-3 cleavage motif DVTD138Y/N, a bipartite nuclear localization signal sequence, and a proline-rich region in the human long isoform. iPLA2beta is widely expressed among mammalian tissues, with highest expression in testis and brain. iPLA2beta prefers to hydrolyze fatty acid at the sn-2 fatty acid substituent but also exhibits phospholipase A1, lysophospholipase, PAF acetylhydrolase, and transacylase activities. iPLA2beta may participate in signaling, apoptosis, membrane phospholipid remodeling, membrane homeostasis, arachidonate release, and exocytotic membrane fusion. Structural features and the existence of multiple splicing variants of iPLA2beta suggest that iPLA2beta may be subject to complex regulatory mechanisms that differ among cell types. Further study of its regulation and interaction with other proteins may yield insight into how its structural features are related to its function.
Prog Nucleic Acid Res Mol Biol 2001
PMID:The molecular biology of the group VIA Ca2+-independent phospholipase A2. 1152 80

Sphingomyelin is a major lipid in the bilayer of subcellular membranes of eukaryotic cells. Different sphingomyelinases catalyze the initial step in the catabolism of sphingomyelin, the hydrolysis to phosphocholine and ceramide. Sphingomyelinases have been postulated to generate ceramide as a lipophilic second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. To elucidate the function of the first cloned Mg(2+)-dependent, neutral sphingomyelinase (nSMase 1) in sphingomyelin catabolism and its potential role in signaling processes in a genetic and molecular approach, we have generated an nSMase 1-null mutant mouse line by gene targeting. The nSMase 1-deficient mice show an inconspicuous phenotype and no accumulation or changed metabolism of sphingomyelin or other lipids, despite grossly reduced nSMase activity in all organs except brain. We also addressed the recent proposal that nSMase 1 possesses lysophospholipase C activity. The unaltered metabolism of lysophosphatidylcholine or lyso-platelet-activating factor excludes the proposed role of nSMase 1 as a lysophospholipase C.
Mol Cell Biol 2002 Jun
PMID:Neutral sphingomyelinase 1 deficiency in the mouse causes no lipid storage disease. 1199

Phospholipase D (PLD; EC 3.1.4.4) has been linked to a number of cellular processes, including Tran membrane signaling and membrane degradation. Four PLD genes (alpha, beta, gamma1, and gamma2) have been cloned from Arabidopsis thalami. They encode isoforms with distinct regulatory and catalytic properties but little is known about their physiological roles. Using cDNA amplified fragment length polymorphism display and RNA blot analysis, we identified Arabidopsis PLDgamma1 and a gene encoding a lysophospholipase (EC 3.1.1.5), lysoPL1, to be differentially expressed during host response to virulent and avirulent pathogen challenge. Examination of the expression pattern of phospholipase genes induced in response to pathogen challenge was undertaken using the lysoPL1 and gene-specific probes corresponding to the PLD isoforms a, beta, and gamma1. Each mRNA class exhibited different temporal patterns of expression after infiltration of leaves with Pseudomonas syringae pv. tomato with or without avrRpm1. PLDalpha was rapidly induced and remained constitutively elevated regardless of treatment. PLDbeta was transiently induced upon pathogen challenge. However, mRNA for the lysoPL1 and PLDgamma1 genes showed enhanced and sustained elevation during an incompatible interaction, in both ndr1 and overexpressing NahG genetic backgrounds. Further evidence for differential engagement of these PLD mRNA during defense responses, other than gene-for-gene interactions, was demonstrated by their response to salicylic acid treatment or wounding. Our results indicate that genes encoding lysoPL1, PLDgamma1, and PLDbeta are induced during early responses to pathogen challenge and, additionally, PLDyl and lysoPL1 are specifically upregulated during gene-for-gene interactions, leading to the hypersensitive response. We discuss the possible role of these genes in plant-pathogen interactions.
Mol Plant Microbe Interact 2002 Aug
PMID:Differential expression of genes encoding Arabidopsis phospholipases after challenge with virulent or avirulent Pseudomonas isolates. 1218 38

Although phospholipase B (PLB) enzymes have been described in eukaryotes from yeasts to mammals, their biological functions are poorly understood. Here we describe the characterization of plb1, one of five genes predicted to encode PLB homologs in the fission yeast, Schizosaccharomyces pombe. The plb1 gene is dispensable under normal growth conditions but required for viability in high-osmolarity media and for normal osmotic stress-induced gene expression. Unlike mutants defective in function for the stress-activated MAP kinase Spc1, plb1Delta cells are not hypersensitive to oxidative or temperature stresses, nor do they undergo a G2-specific arrest in response to osmotic stress. In addition to defects in osmotic stress response, plb1Delta cells exhibit a cold-sensitive defect in nutrient-mediated mating repression, a phenotype reminiscent of mutants in the cyclic AMP (cAMP) pathway. We show that, like plb1Delta cells, mutants in the cAMP pathway are defective for growth in high-osmolarity media, demonstrating a previously unrecognized role for the cAMP pathway in osmotic stress response. Furthermore, we show that gain-of function in the cAMP pathway can rescue the osmosensitive growth defect of plb1Delta cells, suggesting that the cAMP pathway is a potential downstream target of the actions of Plb1 in S. pombe.
Mol Genet Genomics 2003 Apr
PMID:The phospholipase B homolog Plb1 is a mediator of osmotic stress response and of nutrient-dependent repression of sexual differentiation in the fission yeast Schizosaccharomyces pombe. 1271 60


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