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J. Biol. Chem., Vol. 282, Issue 35, 25395-25405, August 31, 2007

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Feedback Inhibition of Pantothenate Kinase Regulates Pantothenol Uptake by the Malaria Parasite^*

Adele M. Lehane, Rosa V. Marchetti, Christina Spry, Donelly A. van Schalkwyk, Rongwei Teng, Kiaran Kirk, and Kevin J. Saliba¹

From the School of Biochemistry and Molecular Biology, Medical School, The Australian National University, Canberra, ACT 0200, Australia

To survive, the human malaria parasite Plasmodium falciparum must acquire pantothenate (vitamin B₅) from the external medium. Pantothenol (provitamin B₅) inhibits parasite growth by competing with pantothenate for pantothenate kinase, the first enzyme in the coenzyme A biosynthesis pathway. In this study we investigated pantothenol uptake by P. falciparum and in doing so gained insights into the regulation of the parasite's coenzyme A biosynthesis pathway. Pantothenol was shown to enter P. falciparum-infected erythrocytes via two routes, the furosemide-inhibited "new permeation pathways" induced by the parasite in the infected erythrocyte membrane (the sole access route for pantothenate) and a second, furosemide-insensitive pathway. Having entered the erythrocyte, pantothenol is taken up by the intracellular parasite via a mechanism showing functional characteristics distinct from those of the parasite's pantothenate uptake mechanism. On reaching the parasite cytosol, pantothenol is phosphorylated and thereby trapped by pantothenate kinase, shown here to be under feedback inhibition control by coenzyme A. Furosemide reduced this inherent feedback inhibition by competing with coenzyme A for binding to pantothenate kinase, thereby increasing pantothenol uptake.

Received for publication, June 5, 2007

^* This work was supported by the Australian National Health and Medical Research Council Grant 224245 and by a grant from the UNICEF/UNDP/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases (TDR). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: School of Biochemistry and Molecular Biology, The Australian National University, Canberra, ACT 0200, Australia. Tel.: 61-2-6125-7549; Fax: 61-2-6125-0313; E-mail: kevin.saliba{at}anu.edu.au.

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