title: Glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase: a unique bifunctional enzyme from Plasmodium falciparum.
abstract: The survival of malaria parasites in human RBCs (red blood cells) depends on the pentose phosphate pathway, both in Plasmodium falciparum and its human host. G6PD (glucose-6-phosphate dehydrogenase) deficiency, the most common human enzyme deficiency, leads to a lack of NADPH in erythrocytes, and protects from malaria. In P. falciparum, G6PD is combined with the second enzyme of the pentose phosphate pathway to create a unique bifunctional enzyme named GluPho (glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase). In the present paper, we report for the first time the cloning, heterologous overexpression, purification and kinetic characterization of both enzymatic activities of full-length PfGluPho (P. falciparum GluPho), and demonstrate striking structural and functional differences with the human enzymes. Detailed kinetic analyses indicate that PfGluPho functions on the basis of a rapid equilibrium random Bi Bi mechanism, where the binding of the second substrate depends on the first substrate. We furthermore show that PfGluPho is inhibited by S-glutathionylation. The availability of recombinant PfGluPho and the major differences to hG6PD (human G6PD) facilitate studies on PfGluPho as an excellent drug target candidate in the search for new antimalarial drugs.
authors: Interdisciplinary Research Center, Justus Liebig University, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.
authors: Esther
authors: E
authors: Jortzik
authors: Boniface M
authors: BM
authors: Mailu
authors: Janina
authors: J
authors: Preuss
authors: Marina
authors: M
authors: Fischer
authors: Lars
authors: L
authors: Bode
authors: Stefan
authors: S
authors: Rahlfs
authors: Katja
authors: K
authors: Becker
mesh_terms: D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D003001:Cloning, Molecular; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000201:enzymology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008288:Malaria / Q000201:enzymology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000201:enzymology
chemical_list: D009097:Multienzyme Complexes; C560097:glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase, Plasmodium falciparum; D005954:Glucosephosphate Dehydrogenase; D002265:Carboxylic Ester Hydrolases; C022363:6-phosphogluconolactonase; D005978:Glutathione