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Article ; Online: Glucose-6-phosphate metabolism in Plasmodium falciparum.

Preuss, Janina / Jortzik, Esther / Becker, Katja

2012 Volume 64, Issue 7, Page(s) 603–611

Abstract: Malaria is still one of the most threatening diseases worldwide. The high drug resistance rates of malarial parasites make its eradication difficult and furthermore necessitate the development of new antimalarial drugs. Plasmodium falciparum is ... ...

Abstract	Malaria is still one of the most threatening diseases worldwide. The high drug resistance rates of malarial parasites make its eradication difficult and furthermore necessitate the development of new antimalarial drugs. Plasmodium falciparum is responsible for severe malaria and therefore of special interest with regard to drug development. Plasmodium parasites are highly dependent on glucose and very sensitive to oxidative stress; two observations that drew interest to the pentose phosphate pathway (PPP) with its key enzyme glucose-6-phosphate dehydrogenase (G6PD). A central position of the PPP for malaria parasites is supported by the fact that human G6PD deficiency protects to a certain degree from malaria infections. Plasmodium parasites and the human host possess a complete PPP, both of which seem to be important for the parasites. Interestingly, there are major differences between parasite and human G6PD, making the enzyme of Plasmodium a promising target for antimalarial drug design. This review gives an overview of the current state of research on glucose-6-phosphate metabolism in P. falciparum and its impact on malaria infections. Moreover, the unique characteristics of the enzyme G6PD in P. falciparum are discussed, upon which its current status as promising target for drug development is based.
MeSH term(s)	Animals ; Antimalarials/pharmacology ; Biological Transport ; Carboxylic Ester Hydrolases/metabolism ; Drug Design ; Glucose-6-Phosphate/metabolism ; Glucosephosphate Dehydrogenase/metabolism ; Glucosephosphate Dehydrogenase Deficiency/metabolism ; Hexokinase/metabolism ; Humans ; NADP/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; Plasmodium falciparum/metabolism
Chemical Substances	Antimalarials ; NADP (53-59-8) ; Glucose-6-Phosphate (56-73-5) ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Hexokinase (EC 2.7.1.1) ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; 6-phosphogluconolactonase (EC 3.1.1.31)
Language	English
Publishing date	2012-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1492141-8
ISSN	1521-6551 ; 1521-6543
ISSN (online)	1521-6551
ISSN	1521-6543
DOI	10.1002/iub.1047
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Article ; Online: An Optimized Dihydrodibenzothiazepine Lead Compound (SBI-0797750) as a Potent and Selective Inhibitor of Plasmodium falciparum and P. vivax Glucose 6-Phosphate Dehydrogenase 6-Phosphogluconolactonase.

Antimicrobial agents and chemotherapy

2022 Volume 66, Issue 4, Page(s) e0210921

Abstract: ... ...

Abstract	In
MeSH term(s)	Antimalarials/pharmacology ; Antimalarials/therapeutic use ; Carboxylic Ester Hydrolases ; Glucose/metabolism ; Glucosephosphate Dehydrogenase/metabolism ; Glucosephosphate Dehydrogenase Deficiency ; Humans ; Hydrogen Peroxide/metabolism ; Malaria ; Malaria, Falciparum/drug therapy ; Malaria, Vivax/drug therapy ; Phosphates ; Plasmodium falciparum/metabolism ; Plasmodium vivax
Chemical Substances	Antimalarials ; Phosphates ; Hydrogen Peroxide (BBX060AN9V) ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; 6-phosphogluconolactonase (EC 3.1.1.31) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.02109-21
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Article ; Online: Glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase: characterization of the Plasmodium vivax enzyme and inhibitor studies.

Haeussler, Kristina / Berneburg, Isabell / Jortzik, Esther / Hahn, Julia / Rahbari, Mahsa / Schulz, Norma / Preuss, Janina / Zapol'skii, Viktor A / Bode, Lars / Pinkerton, Anthony B / Kaufmann, Dieter E / Rahlfs, Stefan / Becker, Katja

Malaria journal

2019 Volume 18, Issue 1, Page(s) 22

Abstract: Background: Since malaria parasites highly depend on ribose 5-phosphate for DNA and RNA synthesis and on NADPH as a source of reducing equivalents, the pentose phosphate pathway (PPP) is considered an excellent anti-malarial drug target. In Plasmodium, ... ...

Abstract	Background: Since malaria parasites highly depend on ribose 5-phosphate for DNA and RNA synthesis and on NADPH as a source of reducing equivalents, the pentose phosphate pathway (PPP) is considered an excellent anti-malarial drug target. In Plasmodium, a bifunctional enzyme named glucose 6-phosphate dehydrogenase 6-phosphogluconolactonase (GluPho) catalyzes the first two steps of the PPP. PfGluPho has been shown to be essential for the growth of blood stage Plasmodium falciparum parasites. Methods: Plasmodium vivax glucose 6-phosphate dehydrogenase (PvG6PD) was cloned, recombinantly produced in Escherichia coli, purified, and characterized via enzyme kinetics and inhibitor studies. The effects of post-translational cysteine modifications were assessed via western blotting and enzyme activity assays. Genetically encoded probes were employed to study the effects of G6PD inhibitors on the cytosolic redox potential of Plasmodium. Results: Here the recombinant production and characterization of PvG6PD, the C-terminal and NADPH-producing part of PvGluPho, is described. A comparison with PfG6PD (the NADPH-producing part of PfGluPho) indicates that the P. vivax enzyme has higher K Conclusion: The characterization of PvG6PD makes this enzyme accessible to further drug discovery activities. In contrast to naturally occurring G6PD variants in the human host that can alter the kinetic properties of the enzyme and thus the redox homeostasis of the cells, the naturally occurring PfGluPho variants studied here are unlikely to have a major impact on the parasites' redox homeostasis. Several classes of inhibitors have been successfully tested and are presently being followed up.
MeSH term(s)	Carboxylic Ester Hydrolases/genetics ; Carboxylic Ester Hydrolases/metabolism ; Cloning, Molecular ; Cytosol/metabolism ; Escherichia coli/metabolism ; Glucosephosphate Dehydrogenase/antagonists & inhibitors ; Glucosephosphate Dehydrogenase/genetics ; Glucosephosphate Dehydrogenase/metabolism ; Kinetics ; Malaria, Vivax/enzymology ; Malaria, Vivax/genetics ; Malaria, Vivax/metabolism ; Multienzyme Complexes/genetics ; Multienzyme Complexes/metabolism ; Oxidation-Reduction ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
Chemical Substances	Multienzyme Complexes ; Protozoan Proteins ; Recombinant Proteins ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; 6-phosphogluconolactonase (EC 3.1.1.31)
Language	English
Publishing date	2019-01-25
Publishing country	England
Document type	Journal Article
ISSN	1475-2875
ISSN (online)	1475-2875
DOI	10.1186/s12936-019-2651-z
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Article: Crystal Structure of the Plasmodium falciparum Thioredoxin Reductase–Thioredoxin Complex

Fritz-Wolf, Karin / Jortzik, Esther / Stumpf, Michaela / Preuss, Janina / Iozef, Rimma / Rahlfs, Stefan / Becker, Katja

Journal of molecular biology. 2013 Sept. 23, v. 425, no. 18

2013

Abstract: Over the last decades, malaria parasites have been rapidly developing resistance against antimalarial drugs, which underlines the need for novel drug targets. Thioredoxin reductase (TrxR) is crucially involved in redox homeostasis and essential for ... ...

Abstract	Over the last decades, malaria parasites have been rapidly developing resistance against antimalarial drugs, which underlines the need for novel drug targets. Thioredoxin reductase (TrxR) is crucially involved in redox homeostasis and essential for Plasmodium falciparum. Here, we report the first crystal structure of P. falciparum TrxR bound to its substrate thioredoxin 1. Upon complex formation, the flexible C-terminal arm and an insertion loop of PfTrxR are rearranged, suggesting that the C-terminal arm changes its conformation during catalysis similar to human TrxR. Striking differences between P. falciparum and human TrxR are a Plasmodium-specific insertion and the conformation of the C-terminal arm, which lead to considerable differences in thioredoxin binding and disulfide reduction. Moreover, we functionally analyzed amino acid residues involved in substrate binding and in the architecture of the intersubunit cavity, which is a known binding site for disulfide reductase inhibitors. Cell biological experiments indicate that P. falciparum TrxR is indeed targeted in the parasite by specific inhibitors with antimalarial activity. Differences between P. falciparum and human TrxR and details on substrate reduction and inhibitor binding provide the first solid basis for structure-based drug development and lead optimization.
Keywords	Plasmodium falciparum ; amino acids ; binding sites ; catalytic activity ; crystal structure ; drugs ; homeostasis ; humans ; parasites
Language	English
Dates of publication	2013-0923
Size	p. 3446-3460.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2013.06.037
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Article ; Online: Identification and characterization of novel human glucose-6-phosphate dehydrogenase inhibitors.

Preuss, Janina / Richardson, Adam D / Pinkerton, Anthony / Hedrick, Michael / Sergienko, Eduard / Rahlfs, Stefan / Becker, Katja / Bode, Lars

Journal of biomolecular screening

2013 Volume 18, Issue 3, Page(s) 286–297

Abstract: Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of the pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphoglucono-δ-lactone with parallel reduction of NADP(+). Several human diseases, including cancer, are associated with ... ...

Abstract	Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of the pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphoglucono-δ-lactone with parallel reduction of NADP(+). Several human diseases, including cancer, are associated with increased G6PD activity. To date, only a few G6PD inhibitors have been available. However, adverse side effects and high IC(50) values hamper their use as therapeutics and basic research probes. In this study, we developed a high-throughput screening assay to identify novel human G6PD (hG6PD) inhibitors. Screening the LOPAC (Sigma-Aldrich; 1280 compounds), Spectrum (Microsource Discovery System; 1969 compounds), and DIVERSet (ChemBridge; 49 971 compounds) small-molecule compound collections revealed 139 compounds that presented ≥50% hG6PD inhibition. Hit compounds were further included in a secondary and orthogonal assay in order to identify false-positives and to determine IC(50) values. The most potent hG6PD inhibitors presented IC(50) values of <4 µM. Compared with the known hG6PD inhibitors dehydroepiandrosterone and 6-aminonicotinamide, the inhibitors identified in this study were 100- to 1000-fold more potent and showed different mechanisms of enzyme inhibition. One of the newly identified hG6PD inhibitors reduced viability of the mammary carcinoma cell line MCF10-AT1 (IC(50) ~25 µM) more strongly than that of normal MCF10-A cells (IC(50) >50 µM).
MeSH term(s)	6-Aminonicotinamide/chemistry ; 6-Aminonicotinamide/pharmacology ; Cell Line, Tumor ; Dehydroepiandrosterone/chemistry ; Dehydroepiandrosterone/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Glucosephosphate Dehydrogenase/antagonists & inhibitors ; Glucosephosphate Dehydrogenase/chemistry ; Glucosephosphate Dehydrogenase/metabolism ; High-Throughput Screening Assays/methods ; Humans ; Inhibitory Concentration 50 ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	Enzyme Inhibitors ; Small Molecule Libraries ; 6-Aminonicotinamide (329-89-5) ; Dehydroepiandrosterone (459AG36T1B) ; Glucosephosphate Dehydrogenase (EC 1.1.1.49)
Language	English
Publishing date	2013-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1433680-7
ISSN	1552-454X ; 1087-0571
ISSN (online)	1552-454X
ISSN	1087-0571
DOI	10.1177/1087057112462131
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Article ; Online: Crystal structure of the Plasmodium falciparum thioredoxin reductase-thioredoxin complex.

Fritz-Wolf, Karin / Jortzik, Esther / Stumpf, Michaela / Preuss, Janina / Iozef, Rimma / Rahlfs, Stefan / Becker, Katja

Journal of molecular biology

2013 Volume 425, Issue 18, Page(s) 3446–3460

Abstract	Over the last decades, malaria parasites have been rapidly developing resistance against antimalarial drugs, which underlines the need for novel drug targets. Thioredoxin reductase (TrxR) is crucially involved in redox homeostasis and essential for Plasmodium falciparum. Here, we report the first crystal structure of P. falciparum TrxR bound to its substrate thioredoxin 1. Upon complex formation, the flexible C-terminal arm and an insertion loop of PfTrxR are rearranged, suggesting that the C-terminal arm changes its conformation during catalysis similar to human TrxR. Striking differences between P. falciparum and human TrxR are a Plasmodium-specific insertion and the conformation of the C-terminal arm, which lead to considerable differences in thioredoxin binding and disulfide reduction. Moreover, we functionally analyzed amino acid residues involved in substrate binding and in the architecture of the intersubunit cavity, which is a known binding site for disulfide reductase inhibitors. Cell biological experiments indicate that P. falciparum TrxR is indeed targeted in the parasite by specific inhibitors with antimalarial activity. Differences between P. falciparum and human TrxR and details on substrate reduction and inhibitor binding provide the first solid basis for structure-based drug development and lead optimization.
MeSH term(s)	Amino Acid Substitution/physiology ; Antimalarials/chemistry ; Antimalarials/metabolism ; Binding Sites/genetics ; Crystallography, X-Ray ; Cysteine/chemistry ; Cysteine/genetics ; Humans ; Models, Biological ; Models, Molecular ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/metabolism ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/metabolism ; Protein Interaction Domains and Motifs/genetics ; Protein Structure, Quaternary ; Protein Structure, Secondary/genetics ; Serine/chemistry ; Serine/genetics ; Thioredoxin-Disulfide Reductase/antagonists & inhibitors ; Thioredoxin-Disulfide Reductase/chemistry ; Thioredoxin-Disulfide Reductase/genetics ; Thioredoxin-Disulfide Reductase/metabolism ; Thioredoxins/chemistry ; Thioredoxins/metabolism
Chemical Substances	Antimalarials ; Multiprotein Complexes ; Serine (452VLY9402) ; Thioredoxins (52500-60-4) ; Thioredoxin-Disulfide Reductase (EC 1.8.1.9) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2013-09-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2013.06.037
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Article ; Online: Characterization of tryptophan aminotransferase 1 of Malassezia furfur, the key enzyme in the production of indolic compounds by M. furfur.

Preuss, Janina / Hort, Wiebke / Lang, Sarah / Netsch, Anette / Rahlfs, Stefan / Lochnit, Günter / Jortzik, Esther / Becker, Katja / Mayser, Peter A

Experimental dermatology

2013 Volume 22, Issue 11, Page(s) 736–741

Abstract: Malassezia yeasts are responsible for the widely distributed skin disease Pityriasis versicolor (PV), which is characterized by a hyper- or hypopigmentation of affected skin areas. For Malassezia furfur, it has been shown that pigment production relies ... ...

Abstract	Malassezia yeasts are responsible for the widely distributed skin disease Pityriasis versicolor (PV), which is characterized by a hyper- or hypopigmentation of affected skin areas. For Malassezia furfur, it has been shown that pigment production relies on tryptophan metabolism. A tryptophan aminotransferase was found to catalyse the initial catalytic step in pigment formation in the model organism Ustilago maydis. Here, we describe the sequence determination, recombinant production and biochemical characterization of tryptophan aminotransferase MfTam1 from M. furfur. The enzyme catalyses the transamination from l-tryptophan to keto acids such as α-ketoglutarate with Km values for both substrates in the low millimolar range. Furthermore, MfTam1 presents a temperature optimum at 40°C and a pH optimum at 8.0. MfTam1 activity is highly dependent on pyridoxal phosphate (PLP), whereas compounds interfering with PLP, such as cycloserine (CS) and aminooxyacetate, inhibit the MfTam1 reaction. CS is known to reverse hyperpigmentation in PV. Thus, the results of the present study give a deeper insight into the role of MfTam1 in PV pathogenesis and as potential target for the development of novel PV therapeutics.
MeSH term(s)	Aminooxyacetic Acid/chemistry ; Cloning, Molecular ; Cycloserine/chemistry ; Escherichia coli/metabolism ; Fungal Proteins/chemistry ; Humans ; Indoles/chemistry ; Keto Acids/chemistry ; Malassezia/enzymology ; Pigmentation ; Pigments, Biological/metabolism ; Pyridoxal Phosphate/chemistry ; Recombinant Proteins/chemistry ; Skin/microbiology ; Tinea Versicolor/microbiology ; Tryptophan/chemistry ; Tryptophan Transaminase/chemistry
Chemical Substances	Fungal Proteins ; Indoles ; Keto Acids ; Pigments, Biological ; Recombinant Proteins ; Aminooxyacetic Acid (14I68GI3OQ) ; Pyridoxal Phosphate (5V5IOJ8338) ; Tryptophan (8DUH1N11BX) ; Cycloserine (95IK5KI84Z) ; Tryptophan Transaminase (EC 2.6.1.27)
Language	English
Publishing date	2013-11
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	1130936-2
ISSN	1600-0625 ; 0906-6705
ISSN (online)	1600-0625
ISSN	0906-6705
DOI	10.1111/exd.12260
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Article ; Online: Plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase is a potential drug target.

Allen, Stacey M / Lim, Erin E / Jortzik, Esther / Preuss, Janina / Chua, Hwa Huat / MacRae, James I / Rahlfs, Stefan / Haeussler, Kristina / Downton, Matthew T / McConville, Malcolm J / Becker, Katja / Ralph, Stuart A

The FEBS journal

2015 Volume 282, Issue 19, Page(s) 3808–3823

Abstract: The malarial parasite Plasmodium falciparum is exposed to substantial redox challenges during its complex life cycle. In intraerythrocytic parasites, haemoglobin breakdown is a major source of reactive oxygen species. Deficiencies in human glucose-6- ... ...

Abstract	The malarial parasite Plasmodium falciparum is exposed to substantial redox challenges during its complex life cycle. In intraerythrocytic parasites, haemoglobin breakdown is a major source of reactive oxygen species. Deficiencies in human glucose-6-phosphate dehydrogenase, the initial enzyme in the pentose phosphate pathway (PPP), lead to a disturbed redox equilibrium in infected erythrocytes and partial protection against severe malaria. In P. falciparum, the first two reactions of the PPP are catalysed by the bifunctional enzyme glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase (PfGluPho). This enzyme differs structurally from its human counterparts and represents a potential target for drugs. In the present study we used epitope tagging of endogenous PfGluPho to verify that the enzyme localises to the parasite cytosol. Furthermore, attempted double crossover disruption of the PfGluPho gene indicates that the enzyme is essential for the growth of blood stage parasites. As a further step towards targeting PfGluPho pharmacologically, ellagic acid was characterised as a potent PfGluPho inhibitor with an IC50 of 76 nM. Interestingly, pro-oxidative drugs or treatment of the parasites with H2O2 only slightly altered PfGluPho expression or activity under the conditions tested. Furthermore, metabolic profiling suggested that pro-oxidative drugs do not significantly perturb the abundance of PPP intermediates. These data indicate that PfGluPho is essential in asexual parasites, but that the oxidative arm of the PPP is not strongly regulated in response to oxidative challenge.
MeSH term(s)	Antimalarials/chemistry ; Antimalarials/pharmacology ; Blood/parasitology ; Carboxylic Ester Hydrolases/antagonists & inhibitors ; Carboxylic Ester Hydrolases/metabolism ; Cytosol/enzymology ; Ellagic Acid/chemistry ; Ellagic Acid/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Gene Knockout Techniques ; Glucose/metabolism ; Glucosephosphate Dehydrogenase/antagonists & inhibitors ; Glucosephosphate Dehydrogenase/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Inhibitory Concentration 50 ; Molecular Docking Simulation ; Molecular Targeted Therapy ; Multienzyme Complexes/antagonists & inhibitors ; Multienzyme Complexes/metabolism ; Oxidative Stress ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/genetics
Chemical Substances	Antimalarials ; Enzyme Inhibitors ; Multienzyme Complexes ; glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase, Plasmodium falciparum ; Ellagic Acid (19YRN3ZS9P) ; Hydrogen Peroxide (BBX060AN9V) ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2015-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.13380
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Article ; Online: Glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase: a unique bifunctional enzyme from Plasmodium falciparum.

Jortzik, Esther / Mailu, Boniface M / Preuss, Janina / Fischer, Marina / Bode, Lars / Rahlfs, Stefan / Becker, Katja

The Biochemical journal

2011 Volume 436, Issue 3, Page(s) 641–650

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, ... ...

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.
MeSH term(s)	Carboxylic Ester Hydrolases/antagonists & inhibitors ; Carboxylic Ester Hydrolases/isolation & purification ; Carboxylic Ester Hydrolases/metabolism ; Cloning, Molecular ; Glucosephosphate Dehydrogenase/antagonists & inhibitors ; Glucosephosphate Dehydrogenase/isolation & purification ; Glucosephosphate Dehydrogenase/metabolism ; Glucosephosphate Dehydrogenase Deficiency/enzymology ; Glutathione/pharmacology ; Humans ; Kinetics ; Malaria/enzymology ; Multienzyme Complexes/antagonists & inhibitors ; Multienzyme Complexes/isolation & purification ; Multienzyme Complexes/metabolism ; Plasmodium falciparum/enzymology
Chemical Substances	Multienzyme Complexes ; glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase, Plasmodium falciparum ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; 6-phosphogluconolactonase (EC 3.1.1.31) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2011-06-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20110170
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Article ; Online: High-throughput screening for small-molecule inhibitors of plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase.

Preuss, Janina / Hedrick, Michael / Sergienko, Eduard / Pinkerton, Anthony / Mangravita-Novo, Arianna / Smith, Layton / Marx, Carolin / Fischer, Elisabeth / Jortzik, Esther / Rahlfs, Stefan / Becker, Katja / Bode, Lars

Journal of biomolecular screening

2012 Volume 17, Issue 6, Page(s) 738–751

Abstract: Plasmodium falciparum causes severe malaria infections in millions of people every year. The parasite is developing resistance to the most common antimalarial drugs, which creates an urgent need for new therapeutics. A promising and attractive target for ...

Abstract	Plasmodium falciparum causes severe malaria infections in millions of people every year. The parasite is developing resistance to the most common antimalarial drugs, which creates an urgent need for new therapeutics. A promising and attractive target for antimalarial drug design is the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) of P. falciparum, which catalyzes the key step in the parasites' pentose phosphate pathway. In this study, we describe the development of a high-throughput screening assay to identify small-molecule inhibitors of recombinant PfGluPho. The optimized assay was used to screen three small-molecule compound libraries-namely, LOPAC (Sigma-Aldrich, 1280 compounds), Spectrum (MicroSource Discovery Systems, 1969 compounds), and DIVERSet (ChemBridge, 49 971 compounds). These pilot screens identified 899 compounds that inhibited PfGluPho activity by at least 50%. Selected compounds were further studied to determine IC(50) values in an orthogonal assay, the type of inhibition and reversibility, and effects on P. falciparum growth. Screening results and follow-up studies for selected PfGluPho inhibitors are presented. Our high-throughput screening assay may provide the basis to identify novel and urgently needed antimalarial drugs.
MeSH term(s)	Antimalarials/pharmacology ; Carboxylic Ester Hydrolases/antagonists & inhibitors ; Cells, Cultured ; Drug Evaluation, Preclinical/methods ; Glucosephosphate Dehydrogenase/antagonists & inhibitors ; Hepatocytes ; High-Throughput Screening Assays ; Humans ; Inhibitory Concentration 50 ; Malaria, Falciparum/drug therapy ; Multienzyme Complexes/antagonists & inhibitors ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/enzymology ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship
Chemical Substances	Antimalarials ; Multienzyme Complexes ; Small Molecule Libraries ; glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase, Plasmodium falciparum ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Carboxylic Ester Hydrolases (EC 3.1.1.-)
Language	English
Publishing date	2012-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1433680-7
ISSN	1552-454X ; 1087-0571
ISSN (online)	1552-454X
ISSN	1087-0571
DOI	10.1177/1087057112442382
Database	MEDical Literature Analysis and Retrieval System OnLINE

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