Trypanosomes and leishmania, the causative agents of African sleeping sickness (Trypanosoma brucei), South American Chagas' disease (T. cruzi) and the different forms of leishmaniasis, have an unprecedented thiol redox metabolism. All of these parasitic protozoa lack glutathione reductase and thioredoxin reductases. The main non-protein thiols are glutathionylspermidine conjugates such as trypanothione [bis(glutathionyl)spermidine] which are kept reduced by the essential flavoenzyme trypanothione reductase.
Our work focuses on irreversible inhibitors and subversive substrates of trypanothione reductase as potential drug candidates. A second approach deals with the detoxification of hydroperoxides. African trypanosomes have 2-Cys-peroxiredoxins and glutathione peroxidase-type enzymes which both obtain their reducing equivalents from the unique cascade composed of trypanothione reductase, trypanothione and tryparedoxin. Site directed mutagenesis and the recent structural analysis revealed that the catalytic mechanism of the parasite glutathione peroxidase-type enzyme differs totally from that of the homologous mammalian selenoenzymes. The role of mono- and dithiol glutaredoxins in the redox metabolism of African trypanosomes is the third current focus.
Aim of our work is to elucidate the unique trypanothione metabolism of trypanosomatids and to contribute to the rational development of new antiparasitic drugs on the basis of specific enzyme inhibitors.
Download BZH Report Krauth-Siegel 2014-2016
Academic Training and Positions
1982 | PhD from the Max-Planck-Institute for Medical Research Heidelberg |
1982-1995 | Staff member at the Institute of Biochemistry II of Heidelberg University |
1989 | Habilitation in Biochemistry |
1995-2003 | Apl. Professor for Biochemistry at Heidelberg University Biochemistry Center (BZH) |
2002 | Call for a professorship for Pharmaceutical Chemistry (Marburg), declined |
since 2003 | Professor for Biochemistry at Heidelberg University Biochemistry Center (BZH) |
German representative of COST Action CM0801 of the EU on “New drugs for neglected diseases” |
Mitarbeiter/-innen
Lab:Room 124
/ Phone: +49 6221 54-4291
Mail:natalie.dirdjaja@bzh.uni-heidelberg.de
Room | Phone | |
---|---|---|
LAB | 124 | +49 6221 54-4291 |
natalie.dirdjaja@bzh.uni-heidelberg.de |
Roldán, A., Comini, M. A., Crispo, M., and Krauth-Siegel, R. L. (2011) Lipoamide dehydrogenase is essential for both bloodstream and procyclic Trypanosoma brucei. Mol. Microbiol. 81, 623-639.
Diechtierow, M. and Krauth-Siegel, R.L. (2011) A tryparedoxin-dependent peroxidase protects
African trypanosomes from membrane damage. Free Radic. Biol. Med. 51, 856-868.
2010
Ceylan S, Seidel V, Ziebart N, Berndt C, Dirdjaja N, Krauth-Siegel RL. The dithiol glutaredoxins of african trypanosomes have distinct roles and are closely linked to the unique trypanothione metabolism.
J Biol Chem. 2010; 285(45):35224-37.
Bakker BM, Krauth-Siegel RL, Clayton C, Matthews K, Girolami M, Westerhoff HV, Michels PA, Breitling R, Barrett MP. The silicon trypanosome.
Parasitology. 2010; 137(9):1333-41. Review.
Muhle-Goll C, Füller F, Ulrich AS, Krauth-Siegel RL. The conserved Cys76 plays a crucial role for the conformation of reduced glutathione peroxidase-type tryparedoxin peroxidase.
FEBS Lett. 2010; 584(5):1027-32.
2009
Eberle C, Burkhard JA, Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds.
ChemMedChem. 2009; 4(12):2034-44.
Comini MA, Dirdjaja N, Kaschel M, Krauth-Siegel RL.Preparative enzymatic synthesis of trypanothione and trypanothione analogues.
Int J Parasitol. 2009; 39(10):1059-62.
Wenzel IN, Wong PE, Maes L, Müller TJ, Krauth-Siegel RL, Barrett MP, Davioud-Charvet E. Unsaturated Mannich bases active against multidrug-resistant Trypanosoma brucei brucei strains.
ChemMedChem. 2009; 4(3):339-51.
Stump B, Eberle C, Schweizer WB, Kaiser M, Brun R, Krauth-Siegel RL, Lentz D, Diederich F. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines.
Chembiochem. 2009; 10(1):79-83.
Wendler A, Irsch T, Rabbani N, Thornalley PJ, Krauth-Siegel RL. Glyoxalase II does not support methylglyoxal detoxification but serves as a general trypanothione thioesterase in African trypanosomes.
Mol Biochem Parasitol. 2009; 163(1):19-27.
Ramos EI, Garza KM, Krauth-Siegel RL, Bader J, Martinez LE, Maldonado RA. 2,3-diphenyl-1,4-naphthoquinone: a potential chemotherapeutic agent against Trypanosoma cruzi.
J Parasitol. 2009; 95(2):461-6.
Cavalli A, Lizzi F, Bongarzone S, Brun R, Luise Krauth-Siegel R, Bolognesi ML.
Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase.
Bioorg Med Chem Lett. 2009; 19(11):3031-5.
Krauth-Siegel RL. Redox signaling and regulation in biology and medicine.
(editors: Jacob BC and Winyard PG), book review in
ChemMedChem. 2009; 4:2123-2127.
2008
Filser M, Comini MA, Molina-Navarro MM, Dirdjaja N, Herrero E, Krauth-Siegel RL. Cloning, functional analysis, and mitochondrial localization of Trypanosoma brucei monothiol glutaredoxin-1.
Biol Chem. 2008; 389(1):21-32.
Krauth-Siegel RL, Comini MA. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism.
Biochim Biophys Acta. 2008; 1780(11):1236-48. Review.
Buchholz K, Comini MA, Wissenbach D, Schirmer RH, Krauth-Siegel RL, Gromer S. Cytotoxic interactions of methylene blue with trypanosomatid-specific disulfide reductases and their dithiol products.
Mol Biochem Parasitol. 2008; 160(1):65-9.
Melchers J, Krauth-Siegel RL, Muhle-Goll C. 1H, 13C, and 15N assignment of the oxidized and reduced forms of T. brucei glutathione peroxidase-type tryparedoxin peroxidase.
Biomolecular NMR Assignments. 2008; 2:65-68.
Comini MA, Rettig J, Dirdjaja N, Hanschmann EM, Berndt C, Krauth-Siegel RL. Monothiol glutaredoxin-1 is an essential iron-sulfur protein in the mitochondrion of African trypanosomes.
J Biol Chem. 2008; 283(41):27785-98.
Melchers J, Diechtierow M, Fehér K, Sinning I, Tews I, Krauth-Siegel RL, Muhle-Goll C. Structural basis for a distinct catalytic mechanism in Trypanosoma brucei tryparedoxin peroxidase.
J Biol Chem. 2008; 283(44):30401-11.
Beig M, Bender F, Oellien F, Rohwer A, Gaßel M, Selzer P, Unden G, Krauth-Siegel RL. Trypanothione reductase: a target protein for a combined in silico and in vitro screening approach.
Flavins and Flavoproteins 2008 (Frago S, Gómez-Moreno C, Medina M eds) Prensas Universitarias Zaragoza. 2008; 5503-8.
Stump B, Eberle C, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities.
Org Biomol Chem. 2008; 6(21):3935-47.
2007
Comini MA, Krauth-Siegel RL, Flohé L. Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes.
Biochem J. 2007, 402(1):43-9.
Melchers J, Dirdjaja N, Ruppert T, Krauth-Siegel RL. Glutathionylation of trypanosomal thiol redox proteins.
J Biol Chem. 2007, 282(12):8678-94.
Krauth-Siegel LR, Comini MA, Schlecker T. The trypanothione system.
Subcell Biochem. 2007, 44:231-51.
Schlecker T, Comini MA, Melchers J, Ruppert T, Krauth-Siegel RL. Catalytic mechanism of the glutathione peroxidase-type tryparedoxin peroxidase of Trypanosoma brucei.
Biochem J. 2007, 405(3):445-54.
Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Betraying the Parasite's Redox System: Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties.
ChemMedChem. 2007, 2(12):1708-1712.
2006
Otero L, Vieites M, Boiani L, Denicola A, Rigol C, Opazo L, Olea-Azar C, Maya JD, Morello A, Krauth-Siegel RL, Piro OE, Castellano E, González M, Gambino D, Cerecetto H. Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets.
J Med Chem. 2006, 49(11):3322-31.
2005
Lee B, Bauer H, Melchers J, Ruppert T, Rattray L, Yardley V, Davioud-Charvet E, Krauth-Siegel RL. Irreversible inactivation of trypanothione reductase by unsaturated mannich bases: a divinyl ketone as key intermediate.
J Med Chem. 2005, 48(23):7400-10.
Meiering S, Inhoff O, Mies J, Vincek A, Garcia G, Kramer B, Dormeyer M, Krauth-Siegel RL. Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis.
J Med Chem. 2005, 48(15):4793-802.
Werner C, Stubbs MT, Krauth-Siegel RL, Klebe G. The crystal structure of Plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs.
J Mol Biol. 2005, 349(3):597-607.
Schlecker T, Schmidt A, Dirdjaja N, Voncken F, Clayton C, Krauth-Siegel RL. Substrate specificity, localization, and essential role of the glutathione peroxidase-type tryparedoxin peroxidases in Trypanosoma brucei.
J Biol Chem. 2005, 280(15):14385-94.
Krauth-Siegel RL, Bauer H, Schirmer RH. Dithiolproteine als Hüter des intrazellulären Redoxmilieus bei Parasiten: alte und neue Wirkstoff-Targets bei Trypanosomiasis und Malaria.
Angew Chem. 2005, 117:698-724.
Krauth-Siegel RL, Bauer H, Schirmer RH. 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. 2005, 44(5):690-715.
Krauth-Siegel RL, Davioud-Charvet E. Trypanothione reductase and other flavoenzymes as targets of antiparasitic drugs.
Flavins and Flavoproteins 2005 (Nishino T, Miura R, Tanokura M, Fukui K Ed.)
ArchiTect Inc Tokyo. 2005, 867-76.
2004
Irsch T, Krauth-Siegel RL.Glyoxalase II of African trypanosomes is trypanothione-dependent.
J Biol Chem. 2004, 279(21):22209-17.
2003
Friemann R, Schmidt H, Ramaswamy S, Forstner M, Krauth-Siegel RL, Eklund H. Structure of thioredoxin from Trypanosoma brucei brucei.
FEBS Lett. 2003, 554:301-305.
Schmidt H, Krauth-Siegel RL. Functional and physicochemical characterization of the thioredoxin system in Trypanosoma brucei.
J Biol Chem. 2003, 278(47): 46329-36.
Müller S, Liebau E, Walter RD, Krauth-Siegel RL. Thiol-based redox metabolism of protozoan parasites.
Trends Parasitol. 2003, 19(7):320-8.
Krauth-Siegel RL, Meiering SK, Schmidt H. The parasite-specific trypanothione metabolism of trypanosoma and leishmania.
Biol Chem. 2003, 384(4):539-49.
Krauth-Siegel RL, Inhoff O. Parasite-specific trypanothione reductase as a drug target molecule.
Parasitol Res. 2003, 90 Suppl 2: 77-85.
Gutierrez-Correa J, Krauth-Siegel RL, Stoppani AO. Phenothiazine radicals inactivate Trypanosoma cruzi dihydrolipoamide dehydrogenase: enzyme protection by radical scavengers.
Free Radic Res. 2003, 37(3):281-91.
2002
Werner C, Stubbs MT, Klebe G, Krauth-Siegel RL. The crystal structure of lipoamide dehydrogenase from Trypanosoma cruzi: A target for the design of new drugs against Chagas’ disease.
Flavins and Flavoproteins 2002, :917-922
Shahi SK, Krauth-Siegel RL, Clayton CE. Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei.
Mol Microbiol. 2002, 43(5):1129-38.
Breidbach T, Scory S, Krauth-Siegel RL, Steverding D. Growth inhibition of bloodstream forms of Trypanosoma brucei by the iron chelator deferoxamine.
Int J Parasitol. 2002, 32(4):473-9.
Krauth-Siegel RL, Schmidt H, Trypanothione and tryparedoxin in ribonucleotide reduction.
Methods Enzymol. 2002, 347:259-66.
Schmidt H., Schmidt A., Krauth-Siegel RL. Der parasitäre Trypanothion-Stoffwechsel-einzigartig und lebensnotwendig.
BIOforum. 2002, 7-8:478-480.
Schmidt A, Clayton C, Krauth-Siegel RL. Silencing of the thioredoxin gene in Trypanosoma brucei brucei.
Mol. Biochem. Parasitol. 2002, 125:207-210
Reckenfelderbäumer, N., Krauth-Siegel, R. L. Catalytic properties, thiol pK value, and redox potential of Trypanosoma brucei tryparedoxin. J. Biol. Chem. 2002, 277, 17548-17555.
Inhoff, O., Richards, J. M., Briet, J. W., Lowe, G., Krauth-Siegel, R. L. Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase. J. Med. Chem. 2002, 45, 4524-4530.
Schmidt, A., Krauth-Siegel, R. L. Enzymes of the trypanothione metabolism as targets for antitrypanosomal drug development. Current Topics Med. Chem. 2002, 2, 1239-1259.
2001
Dormeyer, M., Reckenfelderbäumer, N., Lüdemann, H., Krauth-Siegel, R. L. Trypanothione-dependent synthesis of deoxyribonucleotides by Trypanosoma brucei ribonucleotide reductase. J. Biol. Chem. 2001, 276, 10602-10606.