Glycerol 3-phosphate analogues as metabolic inhibitors in Escherichia coli 3-hydroxy-4-oxobutyl-1-phosphonate, a drug that interferes with normal phosphoglyceride metabolism

Abstract

3-Hydroxy-4-oxobutyl-1-phosphonate, the phosphonic acid analogue of glyceraldehyde 3-phosphate, enters Escherichia coli via the glycerol 3-phosphate transport system. There is no differential effect upon the accumulation of deoxyribonucleic acid, ribonucleic acid, or phosphoglycerides, although the accumulation of proteins was less effected. Examination of the phospholipids revealed that phosphatidylglycerol accumulation was most severely inhibited and cardiolipin accumulation was least affected. Concentrations of glyceraldehyde 3-phosphate and its phosphonic acid analogue that markedly inhibit macromolecular and phosphoglyceride biosynthesis have no effect upon the intracellular nucleoside triphosphate pool size. The phosphonate is a competitive inhibitor of sn-glycerol 3-phosphate in reactions catalyzed by acyl coenzyme A: sn-glycerol-3-phosphate acyltransferase and CDP-diacylglycerol: sn-glycerol-3-phosphate phosphatidyltransferase. A K m mutant for the former enzyme was susceptible to the phosphonate. The phosphonate did not affect acyl coenzyme A:lysophosphatidate acyltransferase activity. Studies with mutant strains ruled out the aerobic glycerol-3-phosphate dehydrogenase, glycerol-3-phosphate synthase, and fructose-1,6-biphosphate aldolase as the primary sites of action.