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, Kevin J. Saliba
2007 Journal of Biological Chemistry  
To survive, the human malaria parasite Plasmodium falciparum must acquire pantothenate (vitamin B 5 ) from the external medium. Pantothenol (provitamin B 5 ) 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.
more » ... alciparum-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. Pantothenate (vitamin B 5 ) is a precursor of coenzyme A (CoA), an obligate enzyme cofactor required in numerous metabolic processes. The five-step conversion of pantothenate to CoA is common to prokaryotes and eukaryotes, although the amino acid sequences of the enzymes involved vary considerably (1). The first step in this pathway is the conversion of pantothenate to 4Ј-phosphopantothenate by pantothenate kinase (PanK). 2
doi:10.1074/jbc.m704610200 pmid:17581817 fatcat:syjpz3adznd63am357v4wuii2m