Skip to main content Accessibility help
×
Home

Inhibition of Plasmodium falciparum lysophospholipase by anti-malarial drugs and sulphydryl reagents

  • R. Zidovetzki (a1), I. W. Sherman (a1), J. Prudhomme (a1) and J. Crawford (a1)

Summary

The activity of lysophospholipase of human erythrocytes increased by about 3 orders of magnitude upon infection with Plasmodium falciparum. The apparent Km for hydrolysis of lysophosphatidylcholine by this enzyme was 50 ± 7μM and the apparent Vmax 6·8±0·6 nmol/h × 106 cells. The activity was Ca2+ independent and had a broad pH maximum at pH 8. The enzyme was insensitive to such anti-malarials as mefloquine and arteether and was only weakly inhibited by chloroquine, with a 50% inhibition concentration (IC50) of 70 mM. The anti-malarials quinine and quinacrine were more efficient inhibitors, with IC50s of 2·6 mM and 0·7 mM, respectively. The sulphydryl agents p–hydroxymercuribenzoate (pHMB) and thimerosal were considerably more potent, inhibiting the plasmodial lysophospholipase with IC50s of 18 μM and 10 μM, respectively. When present at 10 μM prior to invasion, both pHMB and thimerosal arrested the growth and reinvasion capacity of P. falciparum in culture. In a synchronized P. falciparum culture the continuous presence of 5 μM thimerosal dramatically decreased total parasitaemia and, within 4 days, totally abolished the capacity of the surviving parasites to reinvade. Thus the plasmodial lysophospholipase may represent a potential new target for anti-malarial chemotherapy.

Copyright

References

Hide All
Beaumelle, B. D. & Vial, H. J. (1988). Correlation of the efficiency of fatty acid derivatives in suppressing Plasmodium falciparum growth in culture with their inhibitory effect on acyl-CoA synthetase activity. Molecular and Biochemical Parasitology 28, 3942.
Bergelson, L. D., Dyatlovitskaya, E. V., Torkhovskaya, T. I., Sorokina, I. B. & Gorkova, N. P. (1968). Dedifferentiation of phospholipid composition in subcellular particles of cancer cells. FEBS Letters 2, 8793.
Gupta, R. C., Khandelwal, R. L. & Sulakhe, P. V. (1990). Effects of sulfhydryl agents, trifluoperazine, phosphatase inhibitors and tryptic proteolysis on calcineurin isolated from bovine cerebral cortex. Molecular and Cellular Biochemistry 97, 4352.
Hecker, M., Brüne, B., Decker, K. & Ullrich, V. (1989). The sulfhydryl reagent thimerosal elicits human platelet aggregation by mobilization of intracellular calcium and secondary prostaglandin endoperoxide formation. Biochemical and Biophysical Research Communications 159, 961–8.
Hunter, S. A., Burstein, S. & Sedor, C. (1984). Stimulation of prostaglandin synthesis in WI-38 human lung fibroblasts following inhibition of phospholipid acylation by p–hydroxymercuribenzoate. Biochimica et Biophysica Acta 793, 202–12.
Jarvis, A. A., Carin, C. & Dennis, E. A. (1984). Purification and characterization of a lysophospholipase from human amnionic membranes. Journal of Biological Chemistry 259, 15188–95.
Kaever, V., Firla, U. & Resch, K. (1988). Sulfhydryl reagents as model substances for eicosanoid research. Eicosanoids 1, 4957.
Kaever, V., Goppelt-Strübe, M. & Resch, K. (1988). Enhancement of eicosanoid synthesis in mouse peritoneal macrophages by the organic mercury compound thimerosal. Prostaglandins 35, 885902.
Löffler, B.-M., Bohn, E., Hesse, B. & Kunze, H. (1985). Effects of antimalarial drugs on phospholipase A and lysophospholipase activities in plasma membrane, mitochondrial, microsomal and cytosolic subcellular fractions of rat liver. Biochimica et Biophysica Acta 835, 448–55.
Marcus, A. J., Ullman, H. L. & Safier, L. B. (1969). Lipid composition of subcellular particles of human blood platelets. Journal of Lipid Research 10, 108–18.
Metz, S. A. (1986). Putative roles for lysophospholipids as mediators and lipoxygenase-mediated metabolites of arachidonic acid as potentiators of stimulus–secretion coupling: dual mechanisms of p–hydroxymercuribenzoic acid-induced insulin release. Journal of Pharmacology and Experimental Therapeutics 238, 819–32.
Metz, S. A. (1987). Metabolism of lysophospholipids in intact rat islets. The Biochemical Journal 241, 863–9.
Mock, T. & Mann, R. Y. K. (1991). The catabolism of exogenous lysophosphatidylcholine in isolated perfused rat and guinea pig hearts: a comparative study. Biochimica et Biophysica Acta 1084, 167–72.
Papadimitriou, J. C., Carney, D. F. & Shin, M. L. (1991). Inhibitors of membrane lipid metabolism enhance complement-mediated enucleated cell killing through distinct mechanisms. Molecular Immunology 28, 803–9.
Pasvol, G., Wilson, R. J. M., Smalley, M. E. & Brown, J. (1978). Separation of viable schizont infected cells of Plasmodium falciparum from human blood. Annals of Tropical Medicine and Parasitology 65, 87–8.
Quinn, M. T., Kondratenko, N. & Parthasarathy, S. (1991). Analysis of the monocyte chemotactic response to lysophosphatidylcholine: role of lysophospholipase C. Biochimica et Biophysica Acta 1082, 293302.
Sherman, I. W. (1979). Biochemistry of Plasmodium (malarial parasites). Microbiological Reviews 43, 453–95.
Srivastava, A. K. & Chiasson, J.-L. (1989). Comparative characterization of receptor and non-receptor associated protein tyrosine kinases. Biochimica et Biophysica Acta 996, 1318.
Stafford, R. E. & Dennis, E. A. (1988). Lysophospholipids as biosurfactants. Colloids and Surfaces 30, 4764.
Stüning, M., Brom, J. & König, W. (1988). Multiple effects of ethylmercurithiosalicylate on the metabolization of arachidonic acid by human neutrophils. Prostaglandins Leukotrienes and Essential Fatty Acids 32, 17.
Szamel, M. & Resch, K. (1981). Modulation of enzyme activities in isolated lymphocyte plasma membranes by enzymatic modification of phospholipid fatty acids. Journal of Biological Chemistry 256, 11618–23.
Trager, W. & Jensen, J. B. (1976). Human malaria parasites in continuous culture. Science 193, 673–5.
Van Den Bosch, H. & Aarsman, A. J. (1979). A review on methods of phospholipase A2 determination. Agents and Actions 9, 382–9.
Van Iwaarden, P. R., Driessen, A. J. M. & Konings, W. N. (1992). What we can learn from the effects of thiol reagents on transport proteins. Biochimica et Biophysica Acta 1113, 161–70.
Vial, H. J., Ancelin, M.-L., Philippot, J. R. & Thuet, M. J. (1990). Biosynthesis and dynamics of lipids in Plasmodium-infected mature mammalian erythrocytes. Blood Cells 16, 531–55.
Vial, H. J., Ancelin, M. L., Thuet, M. J. & Philippot, J. R. (1989). Phospholipid metabolism in Plasmodium-infected erythrocytes: guidelines for further studies using radioactive precursor incorporation. Parasitology 98, 351–7.
Vial, H. J., Philippot, J. R. & Wallach, D. F. H. (1984). A reevaluation of the status of cholesterol in erythrocytes infected by Plasmodium knowlesi and P. falciparum. Molecular and Biochemical Parasitology 13, 5365.
Vial, H. J., Thuet, M. J., Broussal, J. L. & Philippot, J. R. (1982). Phospholipid biosynthesis by Plasmodium knowlesi-infected erythrocytes: the incorporation of phospholipid precursors and the identification of previously undetected metabolic pathways. Journal of Parasitology 68, 379–91.
Vial, H. J., Thuet, M. J. & Philippot, J. R. (1982). Phospholipid biosynthesis in synchronous Plasmodium falciparum cultures. Journal of Protozoology 29, 258–63.
Weltzien, H. U. (1979). Cytolytic and membrane-perturbing properties of lysophosphatidylcholine. Biochimica et Biophysica Acta 559, 259–87.
Zidovetzki, R. & Sherman, I. W. (1991). Lipid composition of the membranes of malaria-infected erythrocytes and the role of drug-lipid interactions in the mechanism of action of chloroquine and other antimalarials. In Biochemical Protozoology (ed. Coombs, G. H. & North, M. J.), pp. 336–48. London: Taylor & Francis.
Zidovetzki, H., Sherman, I. W. & O'Brien, L. (1993). Inhibition of Plasmodium falciparum phospholipase A2 by chloroquine, quinine and arteether. Journal of Parasitology 79, 565–70.

Keywords

Related content

Powered by UNSILO

Inhibition of Plasmodium falciparum lysophospholipase by anti-malarial drugs and sulphydryl reagents

  • R. Zidovetzki (a1), I. W. Sherman (a1), J. Prudhomme (a1) and J. Crawford (a1)

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.