Inhibition of type I and type II phospholipase A2 by phosphatidyl-ethanolamine linked to polymeric carriers.
We have previously shown that cell surface proteoglycans protect the cell membrane from the action of extracellular phospholipase A2 (PLA2) enzymes [Dan, P., Nitzan, D. W., Dagan, A., Ginsburg, I., and Yedgar, S. (1996) FEBS Lett. 383, 75-78]. Cell-impermeable PLA2 inhibitors (ExPLIs) were prepared by linking phosphatidylethanolamine (PE) to polymeric carriers, specifically, carboxymethylcellulose, heparin, or hyaluronic acid. The structure of these inhibitors enables the incorporation of their PE moiety into the membrane while the polymer remains at the membrane surface. In the present study, we show that the ExPLIs are effective inhibitors of the hydrolysis of different phospholipids in biological (Escherichia coli) and model (phospholipid vesicle) membranes, by diverse types of PLA2 enzymes, specifically human recombinant synovial fluid and C. atrox (type II), as well as Naja mocambique and porcine pancreatic (type I) PLA2. It is proposed that the external polymers of the ExPLIs, which are anchored to the membrane by the PE, mimic the naturally occurring cell surface proteoglycans and similarly protect membranes from the action of exogenous PLA2.
Dan
P
P
Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Dagan
A
A
Krimsky
M
M
Pruzanski
W
W
Vadas
P
P
Yedgar
S
S
D000818:Animals; D002266:Carboxymethylcellulose Sodium / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology*; D003435:Crotalid Venoms / Q000201:enzymology; D054501:Group II Phospholipases A2; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology; D006868:Hydrolysis; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054467:Phospholipases A2; D011108:Polymers / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D013552:Swine; D013582:Synovial Fluid / Q000201:enzymology
D002352:Carrier Proteins; D003435:Crotalid Venoms; D010714:Phosphatidylethanolamines; D011108:Polymers; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D006493:Heparin; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D002266:Carboxymethylcellulose Sodium