Crystal structure of theTrypanosoma cruzi trypanothione reductase·mepacrine complex

Jacoby, E.M.; Schlichting, Ilme; Lantwin, Christina B.; Kabsch, Wolfgang; Krauth‐Siegel, R. Luise

doi:10.1002/(sici)1097-0134(199601)24:1<73::aid-prot5>3.0.co;2-p

Cited by 115 publications

(113 citation statements)

References 28 publications

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“…TR, the most thoroughly studied enzyme of the trypanothione redox metabolism (28), is a key enzyme of the parasite antioxidant defense (44), does not occur in the mammalian host, and has been found to be essential for all trypanosomatids currently studied (15,31,48). The 3-dimensional structure of TR in free form (24,30,54), as well as complexed with substrates (2, 6, 7) and competitive inhibitors (18,25), has been solved. TR and human GR have similar catalytic mechanisms; 14 of the 19 amino acid residues close to the binding site are conserved.…”

mentioning

confidence: 99%

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Holloway

Charman

Fairlamb

et al. 2009

Antimicrob Agents Chemother

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High-throughput screening of 100,000 lead-like compounds led to the identification of nine novel chemical classes of trypanothione reductase (TR) inhibitors worthy of further investigation. Hits from five of these chemical classes have been developed further through different combinations of preliminary structure-activity relationship rate probing and assessment of antiparasitic activity, cytotoxicity, and chemical and in vitro metabolic properties. This has led to the identification of novel TR inhibitor chemotypes that are drug-like and display antiparasitic activity. For one class, a series of analogues have displayed a correlation between TR inhibition and antiparasitic activity. This paper explores the process of identifying, investigating, and evaluating a series of hits from a high-throughput screening campaign.

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confidence: 99%

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Holloway

Charman

Fairlamb

et al. 2009

Antimicrob Agents Chemother

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“…On the contrary, trypanosomatids are reported to be highly susceptible to oxidative stress (8). Correspondingly, their extraordinary metabolism is being discussed as a potential target area of specific trypanocidal agents (1,9,10).…”

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confidence: 99%

Sequence Analysis of the Tryparedoxin Peroxidase Gene fromCrithidia fasciculata and Its Functional Expression in Escherichia coli

Montemartini¹,

Nogoceke²,

Singh

et al. 1998

Journal of Biological Chemistry

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“…Since thioredoxin and glutaredoxin could not yet be detected in trypanosomatids ( [1]; KrauthSiegel et al, unpublished results) we will study if the unique dithiol trypanothione is the donor of reducing equivalents for the parasite ribonucleotide reduction. A link between the trypanothione and the deoxyribonucleotide metabolisms would render inhibitors of trypanothione reductase (TR) even more attractive as potential antiparasitic drugs [26] and nicely fit to the finding that TR is essential for parasite development [27,28].…”

Section: Discussionmentioning

confidence: 99%

Cloning, sequencing and expression of ribonucleotide reductase R2 from Trypanosoma brucei

et al. 1997

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As a first step towards the understanding of the trypanosomal synthesis of deoxyribonucleotides we describe the cloning of the gene of ribonucleotide reductase subunit R2 from 72 brucei hrucei and its overexpression in E. coli. Materials and methods DNA and RNA preparation2;4 l08 long slender 72 brucei cells were suspended in 10 mM Tris-HC1, 250 mM NaCI, 0.5% Nonidet P-40, pH 8.0. After 5 rain incubation on ice the suspension was centrifuged and the cell pellet was homogenized in 200 lal 10 mM Tris-HC1, 10 mM NaC1, 10 mM EDTA, 0.5% SDS, pH 8.0. 50 lag proteinase K were added and the mixture was incubated for 1 h at 37°C. DNA was purified by phenol extraction.RNA was isolated from bloodstream long slender and short stumpy as well as procyclic stages of 72 brucei using the RNA Easy Kit (Qiagen) according to the instructions of the manufacturer.

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Crystal structure of theTrypanosoma cruzi trypanothione reductase·mepacrine complex

Cited by 115 publications

References 28 publications

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Trypanothione Reductase High-Throughput Screening Campaign Identifies Novel Classes of Inhibitors with Antiparasitic Activity

Sequence Analysis of the Tryparedoxin Peroxidase Gene fromCrithidia fasciculata and Its Functional Expression in Escherichia coli

Cloning, sequencing and expression of ribonucleotide reductase R2 from Trypanosoma brucei

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