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Heiner Schirmer Goal To develop affordable and accessible medi- cines for malaria and other diseases of poverty. Background Redox homeostasis is maintained and buffered in cytosolic spaces of most organisms at redox potentials below -250 mV. This guarantees the functionality of thiol and selenol groups also un- der aerobic conditions or in situations of oxidative stress. The biochemical networks that maintain the redox milieu are based in many organisms on a dual system, the glutathione system and the thioredoxin system. We study these systems pri- marily in pathogens including the malarial parasite Plasmodium falciparum and its insect vector Anopheles gambiae. Differences in the proteins of the redox networks among organisms are ex- ploited for the development of species-specific therapeutic agents (Fig.1). Methylene blue, a subversive substrate and inhibitor of disulfide reductases, is currently tested as a partner in antimalarial drug combinations in West Africa. In an- other project, we study the tripeptide glutathione (GSH) as a drug against malignant malnutrition. Glutathione probably acts not only as a redox buf- fer but also as a precursor of the neurotransmit- ters glutamate and glycine (Becker et al 2005). 28 Heiner Schirmer 1964-1966 MD thesis with J.C. Rüegg, MPI für Medizinische Forschung 1966-1970 Postdoctoral fellow with L.H. Noda, Dartmouth Medical School, Hanover, N. H.; internship and residency at hospitals in Heidelberg, Stuttgart, and Karlsruhe 1970-1980 Group leader at Max-Planck-Institut für Medizinische Forschung, Biophysics 1975 Habilitation in Biochemistry 1980-2007 Professor at Heidelberg University; now professor emeritus Studies on Malaria and Malnutrition Research Highlights The phenothiazine drug methylene blue (MB) was the very first synthetic compound to be used in therapeutic medicine, in fact as an antimalarial agent. With respect to the antioxidative networks of the malaria parasite Plasmodium falciparum and its host erythrocytes, MB has several effects: a) it catalyzes auto-oxidation of thiol compounds like thioredoxin, dihydrolipoamide, and glutathione to give disulfides, b) it inhibits the physiological function of the disulfide reductases, and c) it is a substrate of the three P. falciparum disulfide reductases (Fig.2). In each case, the MB-flavoenzyme ensemble acts as a redox-cycling catalyst which consumes NADPH and O as substrates 2 and produces cytotoxic H O (Krauth-Siegel et 2 2 al 2005). When reducing MB, the disulfide reductases utilize the flavin cofactor and not the active site cysteine pair for electron transfer (Fig.1), the catalytic efficiency being in the order of 105 M-1s-1 . Antimalarial MB combination therapies like MBartemisinine and MB-amodiaquine are currently studied by Olaf Müller´s group in clinical trials in Burkina Faso (Zoungrana A, Coulibaly B, Schirmer RH et al submitted; Meissner et al 2005). The combination of MB and amodiaquine is an ethical drug which fulfils the bonaria criteria of a medicine against poverty diseases: this drug combina-
Fig. 1: The active site of thioredoxin reductase as a target of insecticides. The computer model highlights the structural essentials for electron transport in Drosophila melanogaster thioredoxin reductase. The active site of the enzyme from the malaria mosquito Anopheles gambiae is very similar. The electrons flow a long distance from NADPH via FAD, the cysteine pair 57/62 and the cysteine pair 489’/490’ to the disulfide of the substrate thioredoxin (after Gromer et al. 2004). tion is effective, safe, affordable, accessible and available in sufficient dosages (Schirmer 2004). In the last years we have determined a number of characteristics of MB and developed assays for MB in pathophysiological conditions. Human red Fig. 2 Methylene blue as an H 2 O 2 -producing subversive redox-cycler. The enzyme glutathione reductase and other disulfide reductases of the malaria parasite catalyse the reduction of methylene blue to leucomethylene blue. Leucomethylene blue auto-oxidizes instantaneously regenerating MB and producing parasiticidal H 2 O 2 . blood cells with inherited glutathione reductase deficiency (Kamerbeek et al 2007) are studied as host cells of P. falciparum because MB-treated normal RBC act like phenocopies of the GR-de- ficient cells. The clinical studies on MB combination therapies are still supported by a generous initiative of the Dutch DSM Company who granted a Dream Action Award to this project in 2002. Selected Publications 2004 - 2007 Kamerbeek NM, van Zwieten R, de Boer M, Morren G, Vuil H, Bannink N, Lincke C, Dolman KM, Becker K, Schirmer RH, Gromer S, Roos D (2007). Molecular basis of glutathione reductase deficiency in human blood cells. Blood 109, 3560-3566. Becker K, Pons-Kühnemann J, Fechner A, Funk M, Gromer S, Gross HJ, Grünert A, Schirmer RH (2005) Effects of antioxidants on glutathione levels and clinical recovery from the malnutrition syndrome kwashiorkor – a pilot study. Redox Report 10, 204-241. Meissner PE, Mandi G, Coulibaly B et al (2006) Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine. Malaria Journal 5, 84 (pp13). Krauth-Siegel RL, Bauer H, Schirmer RH (2005) Dithiol proteins as guardians of the intracellular redox milieu in parasites: Old and new drug targets in trypanosomes and malaria-causing plasmodia. Angew Chem Int Ed 44, 690-715. Gromer S, Urig S, Becker K (2004) The thioredoxin system - from science to clinic. Med Res Rev 2440-2489. Schirmer RH (2004) Medikamente für die Armen. Spektrum der Wissenschaft Dezember-Heft, pp. 110-113. Awards and Honors 1976 Appointment as a Bicentennial Lecturer in Philadelphia and Boston 2002 Dream Action Award of the Dutch chemical company DSM Heiner Schirmer Biochemie-Zentrum der Universität Heidelberg (BZH) Im Neuenheimer Feld 504 D-69120 Heidelberg Phone Office: +49 (0)6221-54 4165 Phone Lab: +49 (0)6221-54 4175 Fax: +49 (0)6221-54 5586 E-mail: heiner.schirmer@bzh.uni-heidelberg.de Heiner Schirmer 29
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