The Thioredoxin System of the Malaria Parasite Plasmodium falciparum

Kanzok, Stefan M.; Schirmer, R. Heiner; Türbachova, Ivana; Iozef, Rimma; Becker, Katja

doi:10.1074/jbc.m007633200

Cited by 234 publications

(209 citation statements)

References 37 publications

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“…The other possible mechanism would lie on the unique eight-membered ring structure consisted of C-terminal redox active motives in a dimer of the high Mr TrxR. The ring structure of the dyad seems to be more critical in Cys-TrxR than Sel-TrxR for the enzymatic activity (Kanzok et al, 2000). The conformation of TRXR-1 may be compensatory for the Cys substitution for Sel reserving the catalytic activity of the promiscuous enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…In most eukaryotes, TrxR exists as a homodimeric protein in which each high Mr 55 kDa monomer contains an FAD prosthetic group, that captures electrons from NADPH and transfer them to a redox-active disulfide in the N-terminal CVNVGC active site. The dithiol of the reduced CVNVGC active site is oxidized by another subunit's C-terminal redox active motif of the tetrapeptide X-Cys 1 -Cys 2 -X (X is usually Gly or Ser) where Cys 1 and Cys 2 form a rare vicinal disulfide bond during catalytic cycle (Kanzok et al, 2000). The Cys 2 in many TrxRs in mammalian and multicellular eukaryotes is replaced with selenocystein (Sec, U in one-letter code), an analog of cysteine with substitution of sulfur for selenium.…”

Section: Introductionmentioning

confidence: 99%

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Two Thioredoxin Reductases, trxr-1 and trxr-2, Have Differential Physiological Roles in Caenorhabditis elegans

Bandyopadhyay

Hwaang

et al. 2012

Molecules and Cells

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Two Thioredoxin Reductases, trxr-1 and trxr-2, Have Differential Physiological Roles in Caenorhabditis elegans

Bandyopadhyay

Hwaang

et al. 2012

Molecules and Cells

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“…Thioredoxins are also able to perform a dithioldisulfide exchange reaction with glutathione disulfide (GSSG), thereby producing GSH. In organisms possessing GR this re-action can serve as a backup system under conditions of GR insufficiency (15). In insects this normally supportive trait has evolved into a key pathway.…”

mentioning

confidence: 99%

Thioredoxin-2 but Not Thioredoxin-1 Is a Substrate of Thioredoxin Peroxidase-1 from Drosophila melanogaster

Bauer

Kanzok

Schirmer

2002

Journal of Biological Chemistry

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As Drosophila melanogaster does not contain glutathione reductase, the thioredoxin system has a key function for glutathione disulfide reduction in insects (Kanzok, S. M., Fechner, A., Bauer, H., Ulschmid, J. K., Mü ller, H. M., Botella-Munoz, J., Schneuwly, S., Schirmer, R. H., and Becker, K. (2001) Science 291, 643-646). In view of these unique conditions, the protein systems participating in peroxide metabolism and in redox signaling are of special interest. The genes for a second thioredoxin (DmTrx-2) and a thioredoxin peroxidase (DmTPx-1) were cloned and expressed, and the proteins were characterized. In its disulfide form, the 13-kDa protein thioredoxin-2 is a substrate of thioredoxin reductase-1 (K m ‫؍‬ 5.2 M, k cat ‫؍‬ 14.5 s ؊1 ) and in its dithiol form, an electron donor for TPx-1 (K m ‫؍‬ 9 M, k cat ‫؍‬ 5.4 s ؊1 ). DmTrx-2 is capable of reducing glutathione disulfide with a second order rate constant of 170 M ؊1 s ؊1 at pH 7.4 and 25°C. Western blot analysis indicated that this thioredoxin represents up to 1% of the extractable protein of D. melanogaster Schneider cells or whole fruit flies. Recombinant thioredoxin peroxidase-1 (subunit molecular mass ‫؍‬ 23 kDa) was found to be a decameric protein that can efficiently use Trx-2 but not Trx-1 as a reducing substrate. The new electron pathway found in D. melanogaster is also representative for insects that serve as vectors of disease. As a first step we have cloned and functionally expressed the gene that is the orthologue of DmTrx-2 in the malaria mosquito Anopheles gambiae.Aerobic life conditions that are based on metabolizing molecular oxygen are linked inseparably to the occurrence of reactive oxygen species. These compounds are cytotoxic for the organism but even more so for invaders such as microorganisms and tumor cells. The oxidative challenge is counteracted by a shield of enzymatic and non-enzymatic defense systems including superoxide dismutase (2 O 2

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“…This reflects the fact that, in contrast to the mammalian enzymes with very broad substrate specificity, bacterial thioredoxin reductases are much more specific for their disulfide substrate. T. brucei thioredoxin is also reduced by thioredoxin reductase from D. melanogaster with a k cat /K m value 200-fold lower than that reported for the authentic substrate/enzyme couple (23). Taken together, thioredoxin reductases from different organisms accept T. brucei thioredoxin as substrate although with relatively low efficiency.…”

Section: T Brucei Thioredoxin Is Reduced By Different Thioredoxinmentioning

confidence: 79%

Functional and Physicochemical Characterization of the Thioredoxin System in Trypanosoma brucei

Schmidt

Krauth‐Siegel

2003

Journal of Biological Chemistry

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Trypanosoma brucei, the causative agent of African sleeping sickness, possesses a single thioredoxin that has an unusually high pI value of 8.5 and lacks a conserved aspartyl residue claimed to be involved in catalysis in other thioredoxins. Despite these peculiarities, T. brucei thioredoxin behaves like classical thioredoxins. It is reduced by thioredoxin reductases from different species, serves as donor of reducing equivalents for the ribonucleotide reductase of the parasite, and catalyzes the reduction of protein disulfides. The redox potential of ؊267 mV was obtained from protein-protein redox equilibration with Escherichia coli thioredoxin. The pK value of T. brucei thioredoxin was determined by two different methods. Carboxamidomethylation of the reduced protein yielded a pK value of 7.4 and generated mono-alkylated protein. The thiolate absorption at 240 nm resulted in a pK of 7.6 and, based on the extinction coefficient of 11.6 mM ؊1 cm ؊1 , there are two (or three) cysteines titrating with very similar pK values. A thioredoxin reductase has not yet been detected in any organism of the order Kinetoplastida. T. brucei thioredoxin is spontaneously reduced by trypanothione (bis(glutathionyl)spermidine). Obviously, a specific thioredoxin reductase is not required as thioredoxin reduction can be conducted by the parasite-specific trypanothione/ trypanothione reductase system. Trypanosomatids such as Trypanosoma brucei, the causative agent of African sleeping sickness, have a unique thiol metabolism in which the ubiquitous glutathione/glutathione reductase couple is replaced by trypanothione (N 1 ,N 8 -bis(glutathionyl)spermidine), and the flavoenzyme trypanothione reductase (1, 2). The parasite dithiol is much more reactive than glutathione. It is a spontaneous reductant of dehydroascorbate as well as the disulfide forms of glutathione and ovothiol (2). It reduces tryparedoxin, a 16-kDa dithiol protein with a CPPC active site motif, which distantly belongs to the thioredoxin protein family (3). The trypanothione/tryparedoxin couple is the donor of reducing equivalents for the detoxication of hydroperoxides catalyzed by a cascade of proteins that are composed of trypanothione reductase, trypanothione, tryparedoxin, and a peroxiredoxin-type tryparedoxin peroxidase. Tryparedoxin is also involved in the reduction of ribonucleotide reductase (4) and glutathione peroxidase-like parasite peroxidases (5, 6). The trypanothione metabolism is essential for the parasite. Down-regulation of trypanothione reductase in bloodstream T. brucei by more than 90% results in growth arrest and hypersensitivity toward hydrogen peroxide as well as the loss of infectivity in a mouse model (7).Besides tryparedoxin, T. brucei possesses a single classical thioredoxin with a M r of 12,000 and the conserved WCGPC catalytic site (8). The parasite protein is unusual in having a calculated pI value of 8.5 instead of the acidic pI found for most thioredoxins and a conserved functional aspartate (Asp-26 in Escherichia coli thioredoxin) (9, 10)...

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The Thioredoxin System of the Malaria Parasite Plasmodium falciparum

Cited by 234 publications

References 37 publications

Two Thioredoxin Reductases, trxr-1 and trxr-2, Have Differential Physiological Roles in Caenorhabditis elegans

Two Thioredoxin Reductases, trxr-1 and trxr-2, Have Differential Physiological Roles in Caenorhabditis elegans

Thioredoxin-2 but Not Thioredoxin-1 Is a Substrate of Thioredoxin Peroxidase-1 from Drosophila melanogaster

Functional and Physicochemical Characterization of the Thioredoxin System in Trypanosoma brucei

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