A Novel Class of Zinc-Binding Inhibitors for the Phosphatidylcholine-Preferring Phospholipase C from Bacillus cereus

Citations Over TimeTop 22% of 2000 papers

Abstract

The phospholipase C (PLC) isozymes catalyze the hydrolysis of phospholipids to provide diacylglycerol (DAG) and a phosphorylated headgroup. Because DAG has been implicated in cellular signal transduction cascades in mammalian systems, there has been considerable interest in the development of inhibitors of these enzymes. Toward this end, we have discovered that the cyclic N,N'-dihydroxyureas 6-10 inhibit the phosphatidylcholine preferring PLC from Bacillus cereus (PLCBc). This class of inhibitors is believed to function by the bidentate chelation of the N,N'-dihydroxyurea array to one or more of the zinc ions at the active site of the enzyme. Because the affinities of these compounds correlate with the pKaS of the N-OH hydroxyl groups, it is apparent that one or both of the hydroxyl groups must be ionized for effective coordination to the zinc ions. It is also apparent that there may be rather strict steric requirements for these inhibitors.

Related Papers

• → Phosphatidylethanolamine and phosphatidylcholine are sources of diacylglycerol in ras-transformed NIH 3T3 fibroblasts(1999)29 cited
• → Comparison of molecular structure of glycerolipids in rat lung(1978)50 cited
• → The content of diacylglycerol, triacylglycerol and monoacylglycerol and a comparison of the structural and metabolic heterogeneity of diacylglycerols and phosphatidylcholine during rat lung development(1981)37 cited
• → A study of the molecular species of diacylglycerol, phosphatidylcholine and phosphatidylethanolamine and of cholinephosphotransferase and ethanolaminephosphotransferase activities in the type ii pneumocyte(1984)24 cited
• → The role of phosphatidate phosphatase in the biosynthesis of phosphatidylcholine via the CDP‐choline pathway(2012)