Competitive inhibition of lipolytic enzymes. VI. Inhibition of two human phospholipases A 2 by acylamino phospholipid analogues

Abstract

The competitive inhibition of human pancreatic and a mutant human platelet phospholipase A 2 (PLA 2) was investigated using acylamino phospholipid analogues, which are potent competitive inhibitors of porcine pancreatic PLA 2 [De Haas et al. (1990) Biochim. Biophys. Acta 1046, 249–257]. Both the mutant platelet PLA 2 and the human pancreatic PLA 2 are effectively inhibited by these compounds. The enzyme from platelets is most strongly inhibited by compounds with a negatively charged phosphoglycol headgroup. Compounds with a neutral phosphocholine headgroup are only weak inhibitors, whereas an inhibitor with a phosphoethanolamine headgroup shows an intermediate inhibitory capacity. The platelet PLA 2 is most effectively inhibited by negatively charged inhibitors having a relatively short (four or more carbon atoms) alkylchain on position one and a acylamino chain of 14 carbon atoms on position two. For the pancreatic enzyme an inhibitor with a phosphoethanolamine headgroup was more effective than inhibitors with either a phosphocholine or a phosphoglycol headgroup. The chainlength preference of the pancreatic enzyme resembles that of the platelet PLA 2. The largest discrimination in inhibition between the human platelet and the human pancreatic PLA 2 is obtained with inhibitors with a negatively charged phosphoglycol headgroup, an alkyl chain of four carbon atoms on position one and a long acylamino chain of 14–16 carbon atoms on position two. Because the platelet PLA 2 is thought to have several biological functions, specific inhibitors of this enzyme could have important implications in the design of pharmaceutically interesting compounds.