title: Feedback inhibition of pantothenate kinase regulates pantothenol uptake by the malaria parasite.
abstract: 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.
authors.affiliation: School of Biochemistry and Molecular Biology, Medical School, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Adele M
authors.initials: AM
authors.lastname: Lehane
authors.forename: Rosa V
authors.initials: RV
authors.lastname: Marchetti
authors.forename: Christina
authors.initials: C
authors.lastname: Spry
authors.forename: Donelly A
authors.initials: DA
authors.lastname: van Schalkwyk
authors.forename: Rongwei
authors.initials: R
authors.lastname: Teng
authors.forename: Kiaran
authors.initials: K
authors.lastname: Kirk
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Saliba
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D003065:Coenzyme A / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology*; D004910:Erythrocyte Membrane / Q000378:metabolism / Q000469:parasitology; D005665:Furosemide / Q000494:pharmacology; D006801:Humans; D010205:Pantothenic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding / Q000187:drug effects; D015800:Protozoan Proteins / Q000378:metabolism*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D014803:Vitamin B Complex / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015800:Protozoan Proteins; D049994:Sodium Potassium Chloride Symporter Inhibitors; D014803:Vitamin B Complex; D010205:Pantothenic Acid; C007288:dexpanthenol; D005665:Furosemide; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A