Katja Becker

Justus-Liebig-University Giessen, Biochemistry and Molecular Biology, Faculty Member

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Katja Becker studied medicine at Ruprecht Karls University in Heidelberg, Germany, from 1984 to 1991. In 1988 she received her doctorate under the tutelage of R. Heiner Schirmer. The topic of her dissertation was "Glutathione reductase and its apoenzyme: contributions to malaria chemotherapy and to diagnosing FAD deficiencies" (German: Glutathionreduktase und ihr Apoenzym: Beiträge zur Chemotherapie der Malaria und zur Diagnostik von FAD-Mangelzuständen). She completed her university professor qualification (German: Habilitation) in 1996 in the field of biochemistry at the medical faculty of the University of Heidelberg. After completing her medical residency at John Radcliffe Hospital in Oxford and the University Hospital of Basel, she gained clinical and research experience in Nigeria and Ghana and worked as a postdoctoral fellow at the University of Sydney. She qualified as a medical specialist in biochemistry at Heidelberg University in 1998.

She subsequently worked as a senior research fellow at the Biochemistry Center of Heidelberg University. In 1999 Julius Maximilians University in Würzburg appointed her to an associate professorship in the Research Center for Infectious Diseases (German: Zentrum für Infektionsforschung).

In 2000, Justus Liebig University in Giessen, Germany, appointed her to a full professorship in Biochemistry and Molecular Biology at the Interdisciplinary Research Center (German: Interdisziplinäres Forschungszentrum für biowissenschaftliche Grundlagen der Umweltsicherung (IFZ)). Most of her research focus is on the role of oxidative stress and antioxidative protective mechanisms during disease development and on developing new drugs to fight tumorous and infectious diseases, especially malaria.
Supervisors: Prof. Dr. R. Heiner Schirmer
Address: Biochemistry and Molecular Biology
Interdisciplinary Research Center
Justus Liebig University Giessen
Heinrich-Buff-Ring 26-32
35392 Giessen, Germany

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Papers by Katja Becker

Structural and stability characteristics of a monothiol glutaredoxin: Glutaredoxin-like protein 1 from Plasmodium falciparum

by Katja Becker and Timir Tripathi

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Glutathione mediated regulation of oligomeric structure and functional activity of Plasmodium falciparum glutathione S-transferase

by Katja Becker and Timir Tripathi

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The 58 kDa mouse selenoprotein is a BCNU-sensitive thioredoxin reductase

Febs Letters, 1997

The flavoprotein thioredoxin reductase [EC 1.6.4.5] (NADPH+H++thioredoxin-S 2 -> NADP++thioredoxi... more The flavoprotein thioredoxin reductase [EC 1.6.4.5] (NADPH+H++thioredoxin-S 2 -> NADP++thioredoxin-(SH) 2 ) was isolated from mouse Ehrlich ascites tumour (EAT) cells. Like the counterpart from human placenta but unlike the known thioredoxin reductases from non-vertebrate organisms, the mouse enzyme was found to contain 1 equivalent of selenium per subunit of 58 kDa. The K M values were 4.5 JJM for NADPH, 480 uM for DTNB and 36 uM for Escherichia coli thioredoxin, the turnover number with DTNB being =40 s _1 . As mouse is a standard animal model in cancer and malaria research, thioredoxin reductase and glutathione reductase |EC 1.6.4.2] from EAT cells were compared with each other. While both enzymes in their 2-electron reduced form are targets of the cytostatic drug carmustine (BCNU), no immunologic crossreactivity between the two mouse disulfide reductases was observed.

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Determination of antiplasmodial activity and binding affinity of selected natural products towards PfTrxR and PfGR

Natural Product Communications, Aug 1, 2013

In our study, the binding affinities of selected natural products towards PfTrxR, PfGR, human Trx... more In our study, the binding affinities of selected natural products towards PfTrxR, PfGR, human TrxR and human GR were determined using a mass spectrometry based ligand binding assay. The in vitro antimalarial activity and cytotoxicity of these ligands were also determined. Catharanthine, 11-(OH)-coronaridine, hernagine, vobasine and hispolone displayed antiplasmodial activity against PfK1 (IC50 = 0.996-3.63 microg/mL).

High-Throughput Screening for Small-Molecule Inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase 6-Phosphogluconolactonase

Journal of Biomolecular Screening, Apr 11, 2012

Plasmodium falciparum causes severe malaria infections in millions of people every year. The para... more 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.

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¹H, ¹³C, and ¹⁵N sequence-specific resonance assignment and secondary structure of Plasmodium falciparum thioredoxin

Sauerstoff - der aggressive Lebensfunke

Aerztliche Praxis, 1993

Flavins in medicine. An update (minireview)

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Antimalarial Activity of the Ethanol/Alcohol Oxidase System IN VITRO

Among other macrophage secretory products, H2O2 plays an important role in the host&#39;s def... more Among other macrophage secretory products, H2O2 plays an important role in the host&#39;s defense against malaria (Wozencraft et al., Infect. Immun., 43, 664, (1984]. In our in vitro studies on the human malaria parasite Plasmodium falciparum, hydrogen peroxide was produced by the alcohol oxidase-catalyzed reaction ethanol + O2----acetaldehyde + H2O2 (EC 1.1.3.13). At concentrations of 8.7 mM (= 0.5%) ethanol and 0.1 U alcohol oxidase per ml culture, more than 95% of the parasites were irreversibly damaged. Acetaldehyde was found to be parasiticidal per se--probably by releasing immature forms of P. falciparum from erythrocytes--but CH3CHO concentrations as high as 90 mM were required for complete elimination of the parasites. Ethanol (less than 20 mM) or alcohol oxidase alone had no significant effect on parasite viability. As discussed, the ethanol/alcohol oxidase system might be of interest as a potential chemotherapeutic principle, especially since metabolism and pharmacology of the substrates and products are well understood.

Antioxidative Enzyme des Malariaerregers als Targets von Bonaria-Medikamenten

Biospektrum, Feb 1, 2007

Energy Metabolism as an Antimalarial Drug Target

Malaria is a leading cause of mortality and morbidity globally, accounting for 250 million cases ... more Malaria is a leading cause of mortality and morbidity globally, accounting for 250 million cases with almost one million deaths per year, mainly in young children. The causative agent of malaria in humans, Plasmodium falciparum, undergoes a complex life cycle, both in the human host and in the Anopheles mosquito vector. In the human host, the merozoite life stage of P. falciparum is responsible for the characteristic symptoms. This life stage requires glycolysis for its energy generation; indeed, selective inhibitors of P. falciparum glycolytic enzymes have been shown to halt proliferation of the parasite. The inhibition of lactate dehydrogenase by gossypol derivatives, as well as by azole-based compounds, also exhibits antimalarial activity. In agreement with these observations, human pyruvate kinase deficiency exerts a protective effect against malaria infection and replication. This phenomenon is comparable to glucose 6-phosphate dehydrogenase deficiency, and indicates that an inhibition of the glycolytic pathway of the host–parasite cell unit is a valuable target for antimalarial strategies. Several enzymes of the glycolytic pathway that convert glucose to lactate have been extensively studied in the context of structure-based inhibitor design. This chapter summarizes the current knowledge of the function, structure, and regulation of important glycolytic enzymes of P. falciparum in comparison to their human counterparts, and elucidates their potential as drug targets.

Malaria – mit neuen Methoden gegen eine alte Geißel der Menschheit

Ellagic acid derivatives as P. falciparum glutathione S-transferase inhibitors and potential antimalarial drugs

Warum haben Kinder in Afrika so oft Fieber?

Glutathione-reductase deficiency. A new malaria-protective mutation?

Clinical Biochemistry, 2009

Conformational stability and energetics of Plasmodium falciparum glutaredoxin

Biochimie, Mar 31, 2010

Glutaredoxins (Grxs), redox-active proteins with a typical -CPYC motif at their active sites, are... more Glutaredoxins (Grxs), redox-active proteins with a typical -CPYC motif at their active sites, are involved in redox-regulatory processes and antioxidant defenses. The human malarial parasite Plasmodium falciparum possess a classical glutaredoxin (PfGrx) as well as a number of Grx-like proteins. In the present study, we investigated the unfolding energetics and conformational stability of PfGrx, using isothermal guanidine hydrochloride-induced and pH-dependent thermal denaturation. Reversible unfolding can be modeled using a two-state transition between the native and unfolded states. The structural topology of the protein was stable over a wide pH range from 3.0 to 11.0. Although the protein was thermally stable, it exhibited a small free energy of 1.56 kcal mol À1 at 25 C. The thermostability of PfGrx reached its maximum at pH 8.0, with a T m of 76.2 C and a DH m of 119 kcal mol À1 . To elucidate the factors underlying the thermostability, a protein stability curve was generated. Maximum stability occurred at around 47 C, where the DG H2O D value was 4.30 kcal mol À1 . The high structural stability over a broad pH range, together with the capacity to endure very high temperatures, supports the notion that Grx can withstand a wide variety of conditions, allowing it to play a key role in cellular redox homeostasis. To the best of our knowledge, this work represents the first attempt to understand the energetic characteristics of a glutaredoxin in relation to accompanying structural changes.

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Plasmoredoxin, a novel redox-active protein unique for malarial parasites

European Journal of Biochemistry, Mar 1, 2003

Thioredoxins are a group of small redox-active proteins involved in cellular redox regulatory pro... more Thioredoxins are a group of small redox-active proteins involved in cellular redox regulatory processes as well as antioxidant defense. Thioredoxin, glutaredoxin, and tryparedoxin are members of the thioredoxin superfamily and share structural and functional characteristics. In the malarial parasite, Plasmodium falciparum, a functional thioredoxin and glutathione system have been demonstrated and are considered to be attractive targets for antimalarial drug development.

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Characterization of the 26S proteasome network in Plasmodium falciparum

Scientific reports, 2015

In eukaryotic cells, the ubiquitin-proteasome system as a key regulator of protein quality contro... more In eukaryotic cells, the ubiquitin-proteasome system as a key regulator of protein quality control is an excellent drug target. We therefore aimed to analyze the 26S proteasome complex in the malaria parasite Plasmodium falciparum, which still threatens almost half of the world's population. First, we established an affinity purification protocol allowing for the isolation of functional 26S proteasome complexes from the parasite. Subunit composition of the proteasome and component stoichiometry were studied and physiologic interacting partners were identified via in situ protein crosslinking. Furthermore, intrinsic ubiquitin receptors of the plasmodial proteasome were determined and their roles in proteasomal substrate recognition were analyzed. Notably, PfUSP14 was characterized as a proteasome-associated deubiquitinase resulting in the concept that targeting proteasomal deubiquitinating activity in P. falciparum may represent a promising antimalarial strategy. The data provide...

Quantitative proteomics of Plasmodium falciparum protein expression following drug exposure

International Journal for Parasitology

Diderot’s Molecules – Eine Installation der Jungen Akademie

Nova acta Leopoldina: Abhandlungen der Kaiserlich Leopoldinisch-Carolinisch Deutschen Akademie der Naturforscher

Structural and stability characteristics of a monothiol glutaredoxin: Glutaredoxin-like protein 1 from Plasmodium falciparum

by Katja Becker and Timir Tripathi

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Glutathione mediated regulation of oligomeric structure and functional activity of Plasmodium falciparum glutathione S-transferase

by Katja Becker and Timir Tripathi

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The 58 kDa mouse selenoprotein is a BCNU-sensitive thioredoxin reductase

Febs Letters, 1997