Document Detail

Activation of human neutrophil NADPH oxidase by phosphatidic acid or diacylglycerol in a cell-free system. Activity of diacylglycerol is dependent on its conversion to phosphatidic acid.
MedLine Citation:
PMID:  10428791     Owner:  NLM     Status:  MEDLINE    
The superoxide-generating neutrophil NADPH oxidase can be activated in cell-free reconstitution systems by several agonists, most notably arachidonic acid and the detergent sodium dodecyl sulfate. In this study, we show that both phosphatidic acids and diacylglycerols can serve separately as potent, physiologic activators of NADPH oxidase in a cell-free system. Stimulation of superoxide generation by these lipids was dependent upon both Mg(2+) and agonist concentration. Activation of NADPH oxidase by phosphatidic acids did not appear to require their conversion to corresponding diacylglycerols by phosphatidate phosphohydrolase, since diacylglycerols were much slower than phosphatidic acids to activate the system and required the presence of ATP. Stimulation of the oxidase by dioctanoylglycerol proved to be by a means other than the activation of protein kinase C. Instead, dioctanoylglycerol was converted to dioctanoylphosphatidic acid by an endogenous diacylglycerol kinase present in the cell-free reaction system. This conversion was sensitive to the diacylglycerol kinase inhibitor R59949 and explains the markedly slower kinetics of activation and the novel ATP requirement seen with dioctanoylglycerol. The level of dioctanoylphosphatidic acid formed was suboptimal for NADPH oxidase activation but could synergize with the unmetabolized dioctanoylglycerol to activate superoxide generation.
R W Erickson; P Langel-Peveri; A E Traynor-Kaplan; P G Heyworth; J T Curnutte
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  274     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1999 Aug 
Date Detail:
Created Date:  1999-09-02     Completed Date:  1999-09-02     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  22243-50     Citation Subset:  IM    
Department of Immunology, Genentech, Inc., South San Francisco, California 94080, USA.
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MeSH Terms
Cell-Free System
Diacylglycerol Kinase / antagonists & inhibitors
Diglycerides / metabolism*,  pharmacology
Drug Synergism
Enzyme Activation
NADPH Oxidase / metabolism*
Neutrophils / enzymology*
Phosphatidic Acids / metabolism*,  pharmacology
Piperidines / pharmacology
Quinazolines / pharmacology
Second Messenger Systems
Superoxides / metabolism
Grant Support
Reg. No./Substance:
0/Diglycerides; 0/Phosphatidic Acids; 0/Piperidines; 0/Quinazolines; 0/Quinazolinones; 102731-57-7/dioctanoylphosphatidic acid; 11062-77-4/Superoxides; 120166-69-0/R 59949; EC Oxidase; EC Kinase

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