The crystal structure of trypanothione reductase from the human pathogen <i>Trypanosoma cruzi</i> at 2.3 Å resolution

Zhang, Yihong; Bond, Charles S.; Bailey, Susan; Cunningham, Mark L.; Fairlamb, Alan H.; Hunter, William N.

doi:10.1002/pro.5560050107

Cited by 105 publications

(95 citation statements)

References 52 publications

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“…The overall topology of this enzyme is similar to that of other pyridine nucleotide disulfide oxidoreductases, particularly glutathione reductases (30)(31)(32)(33)(34)(35), and is in agreement with earlier modeling studies of high-M r TrxRs (15). Interestingly, all of the residues in glutathione reductase responsible for substrate recognition are structurally conserved in rTrxR1, even though rTrxR1 cannot directly reduce oxidized glutathione.…”

supporting

confidence: 88%

Crystal structures of oxidized and reduced mitochondrial thioredoxin reductase provide molecular details of the reaction mechanism

Biterova

Turanov

Gladyshev

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

107

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Thioredoxin reductase (TrxR) is an essential enzyme required for the efficient maintenance of the cellular redox homeostasis, particularly in cancer cells that are sensitive to reactive oxygen species. In mammals, distinct isozymes function in the cytosol and mitochondria. Through an intricate mechanism, these enzymes transfer reducing equivalents from NADPH to bound FAD and subsequently to an active-site disulfide. In mammalian TrxRs, the dithiol then reduces a mobile C-terminal selenocysteine-containing tetrapeptide of the opposing subunit of the dimer. Once activated, the C-terminal redox center reduces a disulfide bond within thioredoxin. In this report, we present the structural data on a mitochondrial TrxR, TrxR2 (also known as TR3 and TxnRd2). Mouse TrxR2, in which the essential selenocysteine residue had been replaced with cysteine, was isolated as a FAD-containing holoenzyme and crystallized (2.6 Å; R ‫؍‬ 22.2%; Rfree ‫؍‬ 27.6%). The addition of NADPH to the TrxR2 crystals resulted in a color change, indicating reduction of the active-site disulfide and formation of a species presumed to be the flavin-thiolate charge transfer complex. Examination of the NADP(H)-bound model (3.0 Å; R ‫؍‬ 24.1%; R free ‫؍‬ 31.2%) indicates that an active-site tyrosine residue must rotate from its initial position to stack against the nicotinamide ring of NADPH, which is juxtaposed to the isoalloxazine ring of FAD to facilitate hydride transfer. Detailed analysis of the structural data in conjunction with a model of the unusual C-terminal selenenylsulfide suggests molecular details of the reaction mechanism and highlights evolutionary adaptations among reductases.hioredoxins are the major cellular protein disulfide reductases and are responsible for the regulation of numerous biochemical processes within the cell (1). These proteins are maintained in a reduced state by thioredoxin reductases (TrxR), homodimeric f lavoproteins that catalyze the NADPHdependent reduction of thioredoxins (2, 3).Two forms of TrxRs have evolved with related but distinct modes of catalysis (2-5). Low-M r TrxRs (M r Ϸ 35 kDa) are typically found in prokaryotes, archaea, plants, and lower eukaryotes, whereas high-M r TrxRs (M r Ϸ 55 kDa) are observed in higher eukaryotes. To date, only the green algae Chlamydomonas reinhardtii has been shown to contain both a low-and a high-M r TrxR (6).The general features of catalysis are retained in both low-and high-M r TrxR (2, 4). TrxR transfers reducing equivalents from NADPH to its bound FAD, ultimately leading to the reduction of an active-site disulfide. In low-M r TrxRs, the catalytic cycle requires a large conformational change after dithiol activation (4,7,8). In high-M r TrxR, the active-site dithiol reduces a third redox active center in the highly mobile C terminus of the opposing subunit. This third group is responsible for the reduction of the disulfide bond within thioredoxin. Its nature is species-specific and ranges from a C-X-X-X-X-C disulfide in Plasmodium falciparum (9) to a vicinal disulfid...

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supporting

confidence: 88%

Crystal structures of oxidized and reduced mitochondrial thioredoxin reductase provide molecular details of the reaction mechanism

Biterova

Turanov

Gladyshev

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

107

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“…Antiparallel ␤-sheet structures are known to stabilize proteins, especially when the number of strands present is greater than 2 (62). MerA has five ␤-strands within its dimerization domain (48). Therefore, the presence of a proline residue at the end of the ␤-strand of box2 adds stability to the antiparallel ␤-sheets, which may help to stabilize the MerA ATII-LCL structure at high temperatures.…”

Section: Discussionmentioning

confidence: 99%

“…1 and 5A). This domain, which is present in ATII-LCL MerA, is known to be conserved among the homodimer pyridine nucleotide-disulfide oxidoreductases (48). The second box (box2), however, is located within the dimerization sequence arranged in a ␤-strand structure ( Figs.…”

Section: Location Of the Glutamic Residues And The Two Basic/proline mentioning

confidence: 99%

A Novel Mercuric Reductase from the Unique Deep Brine Environment of Atlantis II in the Red Sea

Sayed

Ghazy

Ferreira

et al. 2014

Journal of Biological Chemistry

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Background: Molecular features underlying enzyme function in extreme environments are poorly understood. Results: Identification of the basis for thermostability, halophilicity, and detoxification activity in a mercuric reductase from hot deep-sea brine. Conclusion: A small number of structural modifications accounts for the enzyme's robustness. Significance: This work defines novel adaptations that enable enzymes to cope with multiple abiotic stressors simultaneously.

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“…Earlier, a four-domain model was constructed along the amino acid sequence (6), followed by a three-domain model based on hydrophobic cores (7)(8)(9). Domain I is composed of two segments and binds FAD, domain II binds with NADPH, and domain III forms an interface with partner subunit.…”

Section: Overall Structurementioning

confidence: 99%

Modeled structure of trypanothione reductase of Leishmania infantum

Singh

Sarkar²,

Jagannadham³

et al. 2008

BMB Reports

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Trypanothione reductase is an important target enzyme for structure-based drug design against Leishmania. We used homology modeling to construct a three-dimensional structure of the trypanothione reductase (TR) of Leishmania infantum. The structure shows acceptable Ramachandran statistics and a remarkably different active site from glutathione reductase(GR). Thus, a specific inhibitor against TR can be designed without interfering with host (human) GR activity. [BMB reports 2008; 41(6): 444-447]

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The crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 Å resolution

Cited by 105 publications

References 52 publications

Crystal structures of oxidized and reduced mitochondrial thioredoxin reductase provide molecular details of the reaction mechanism

Crystal structures of oxidized and reduced mitochondrial thioredoxin reductase provide molecular details of the reaction mechanism

A Novel Mercuric Reductase from the Unique Deep Brine Environment of Atlantis II in the Red Sea

Modeled structure of trypanothione reductase of Leishmania infantum

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