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.
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PMID:Lysophosphatidic acid, alkylglycerophosphate and alkylacetylglycerophosphate increase the neuronal nuclear acetylation of 1-acyl lysophosphatidyl choline by inhibition of lysophospholipase. 1049 77

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

Neuropathy target esterase (NTE) is an endoplasmic reticulum-anchored protein conserved across species. The N-terminal regulatory region of NTE contains three cyclic nucleotide binding domains while the C-terminal catalytic domain has a patatin domain. The NTE gene is expressed in mouse early at embryonic day 7 and its expression is maintained throughout embryonic development. NTE protein is mainly distributed in the nervous system with a pattern that is more restricted to large neurons in older animals. NTE regulates phospholipid metabolism and is known to be a phospholipase B. Knockout of NTE is embryonic lethal in mice, indicating that NTE is essential for embryonic survival. Neuronal specific NTE knockouts survive to adulthood, but show vacuolation and neuronal loss characteristic of neurodegenerative diseases. Recently, mutations in human NTE have been shown to cause a hereditary spastic paraplegia called NTE-related motor neuron disorder, suggesting a critical role for NTE in the nervous system.
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PMID:Neuropathy target esterase: an essential enzyme for neural development and axonal maintenance. 2000 30