Document Detail

A metabolic path for the degradation of lysophosphatidic acid, an inhibitor of lysophosphatidylcholine lysophospholipase, in neuronal nuclei of cerebral cortex.
MedLine Citation:
PMID:  10601695     Owner:  NLM     Status:  MEDLINE    
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.
R R Baker; H y Chang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1483     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2000-03-31     Completed Date:  2000-03-31     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  58-68     Citation Subset:  IM    
Department of Biochemistry, Room 5202, Medical Sciences Bldg., University of Toronto, Toronto, Ont., Canada.
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MeSH Terms
Cell Nucleus / metabolism
Cerebral Cortex / metabolism*
Ethylmaleimide / pharmacology
Glycerides / metabolism
Hydrogen-Ion Concentration
Lysophospholipase / antagonists & inhibitors*
Lysophospholipids / metabolism*
Monoacylglycerol Lipases / metabolism
Neurons / metabolism
Phosphoric Monoester Hydrolases / metabolism
Subcellular Fractions / enzymology,  metabolism
Reg. No./Substance:
0/Glycerides; 0/Lysophospholipids; 128-53-0/Ethylmaleimide; EC 3.1.1.-/lysophosphatidic acid-hydrolysing lysophospholipase; EC Lipases; EC; EC 3.1.3.-/Phosphoric Monoester Hydrolases

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