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

Published online by Cambridge University Press:  06 April 2009

R. Zidovetzki ,
I. W. Sherman ,
J. Prudhomme  and
J. Crawford
R. Zidovetzki
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
I. W. Sherman
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
J. Prudhomme
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
J. Crawford
Affiliation:
Departments of Biology and Neuroscience, University of California, Riverside, CA 92521, USA
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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.

Keywords

malariathimerosalsulphydryl reagentsPlasmodium falciparum
Type
Research Article
Information
Parasitology , Volume 108 , Issue 3 , April 1994 , pp. 249 - 255
Copyright
Copyright © Cambridge University Press 1994

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References

REFERENCES

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, 39–42.CrossRefGoogle ScholarPubMed
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, 87–93.CrossRefGoogle ScholarPubMed
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, 43–52.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Kaever, V., Firla, U. & Resch, K. (1988). Sulfhydryl reagents as model substances for eicosanoid research. Eicosanoids 1, 49–57.Google ScholarPubMed
Kaever, V., Goppelt-Strübe, M. & Resch, K. (1988). Enhancement of eicosanoid synthesis in mouse peritoneal macrophages by the organic mercury compound thimerosal. Prostaglandins 35, 885–902.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
Metz, S. A. (1987). Metabolism of lysophospholipids in intact rat islets. The Biochemical Journal 241, 863–9.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
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, 293–302.CrossRefGoogle ScholarPubMed
Sherman, I. W. (1979). Biochemistry of Plasmodium (malarial parasites). Microbiological Reviews 43, 453–95.CrossRefGoogle ScholarPubMed
Srivastava, A. K. & Chiasson, J.-L. (1989). Comparative characterization of receptor and non-receptor associated protein tyrosine kinases. Biochimica et Biophysica Acta 996, 13–18.CrossRefGoogle ScholarPubMed
Stafford, R. E. & Dennis, E. A. (1988). Lysophospholipids as biosurfactants. Colloids and Surfaces 30, 47–64.CrossRefGoogle Scholar
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, 1–7.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Trager, W. & Jensen, J. B. (1976). Human malaria parasites in continuous culture. Science 193, 673–5.CrossRefGoogle ScholarPubMed
Van Den Bosch, H. & Aarsman, A. J. (1979). A review on methods of phospholipase A2 determination. Agents and Actions 9, 382–9.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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, 53–65.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Vial, H. J., Thuet, M. J. & Philippot, J. R. (1982). Phospholipid biosynthesis in synchronous Plasmodium falciparum cultures. Journal of Protozoology 29, 258–63.CrossRefGoogle ScholarPubMed
Weltzien, H. U. (1979). Cytolytic and membrane-perturbing properties of lysophosphatidylcholine. Biochimica et Biophysica Acta 559, 259–87.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed