Glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase: a unique bifunctional enzyme from Plasmodium falciparum. 2011

Esther Jortzik, and Boniface M Mailu, and Janina Preuss, and Marina Fischer, and Lars Bode, and Stefan Rahlfs, and Katja Becker
Interdisciplinary Research Center, Justus Liebig University, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.

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.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008288 Malaria A protozoan disease caused in humans by four species of the PLASMODIUM genus: PLASMODIUM FALCIPARUM; PLASMODIUM VIVAX; PLASMODIUM OVALE; and PLASMODIUM MALARIAE; and transmitted by the bite of an infected female mosquito of the genus ANOPHELES. Malaria is endemic in parts of Asia, Africa, Central and South America, Oceania, and certain Caribbean islands. It is characterized by extreme exhaustion associated with paroxysms of high FEVER; SWEATING; shaking CHILLS; and ANEMIA. Malaria in ANIMALS is caused by other species of plasmodia. Marsh Fever,Plasmodium Infections,Remittent Fever,Infections, Plasmodium,Paludism,Fever, Marsh,Fever, Remittent,Infection, Plasmodium,Plasmodium Infection
D009097 Multienzyme Complexes Systems of enzymes which function sequentially by catalyzing consecutive reactions linked by common metabolic intermediates. They may involve simply a transfer of water molecules or hydrogen atoms and may be associated with large supramolecular structures such as MITOCHONDRIA or RIBOSOMES. Complexes, Multienzyme
D010963 Plasmodium falciparum A species of protozoa that is the causal agent of falciparum malaria (MALARIA, FALCIPARUM). It is most prevalent in the tropics and subtropics. Plasmodium falciparums,falciparums, Plasmodium
D002265 Carboxylic Ester Hydrolases Enzymes which catalyze the hydrolysis of carboxylic acid esters with the formation of an alcohol and a carboxylic acid anion. Carboxylesterases,Ester Hydrolases, Carboxylic,Hydrolases, Carboxylic Ester
D003001 Cloning, Molecular The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells. Molecular Cloning
D005954 Glucosephosphate Dehydrogenase Glucose-6-Phosphate Dehydrogenase,Dehydrogenase, Glucose-6-Phosphate,Dehydrogenase, Glucosephosphate,Glucose 6 Phosphate Dehydrogenase
D005955 Glucosephosphate Dehydrogenase Deficiency A disease-producing enzyme deficiency subject to many variants, some of which cause a deficiency of GLUCOSE-6-PHOSPHATE DEHYDROGENASE activity in erythrocytes, leading to hemolytic anemia. Deficiency of Glucose-6-Phosphate Dehydrogenase,Deficiency, GPD,Deficiency, Glucosephosphate Dehydrogenase,G6PD Deficiency,GPD Deficiency,Glucose 6 Phosphate Dehydrogenase Deficiency,Glucose-6-Phosphate Dehydrogenase Deficiency,Glucosephosphate Dehydrogenase Deficiencies,Hemolytic Anemia Due to G6PD Deficiency,Deficiencies, G6PD,Deficiencies, GPD,Deficiencies, Glucose-6-Phosphate Dehydrogenase,Deficiencies, Glucosephosphate Dehydrogenase,Deficiency of Glucose 6 Phosphate Dehydrogenase,Deficiency, G6PD,Deficiency, Glucose-6-Phosphate Dehydrogenase,Dehydrogenase Deficiencies, Glucose-6-Phosphate,Dehydrogenase Deficiencies, Glucosephosphate,Dehydrogenase Deficiency, Glucose-6-Phosphate,Dehydrogenase Deficiency, Glucosephosphate,G6PD Deficiencies,GPD Deficiencies,Glucose-6-Phosphate Dehydrogenase Deficiencies
D005978 Glutathione A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides. Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

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