Affinage · Plasmodium

TRXR

PF3D7_0923800 · thioredoxin reductase

Annotated
2026-09-08
62 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PF3D7_0923800 (TRXR) is a high-Mr flavoenzyme thioredoxin reductase that constitutes the terminal electron-donating step of the P. falciparum thioredoxin redox system, and it is essential for erythrocytic-stage survival (PMID:9368022, PMID:12004069). Catalysis proceeds by electron transfer from NADPH through FAD to an N-terminal redox-active Cys88/Cys93 disulfide, with His509 serving as the active-site base whose function is enhanced by Glu514 acting as an acid-base dyad (PMID:9368022, PMID:16950793). Electrons are then relayed to the C-terminal Cys535/Cys540 pair, which forms a 20-membered type II disulfide ring required specifically for reduction of the physiological substrate thioredoxin rather than for FAD-proximal chemistry (PMID:9563503, PMID:24400600); within this ring, Cys535 acts as the electrophile/leaving group and Cys540 as the attacking nucleophile in the intramolecular dithiol-disulfide interchange (PMID:29485860). The enzyme is a head-to-tail homodimer with intersubunit active sites, such that the N-terminal cysteines of one subunit pair with the C-terminal cysteines of the opposite subunit (PMID:11022050). TRXR reduces its cognate P. falciparum thioredoxin with high catalytic efficiency and marked substrate preference over model thioredoxins (PMID:11013257, PMID:11223129), and crystal structures of the free enzyme and of the TRXR–thioredoxin 1 complex reveal a Plasmodium-specific dimer interface and a flexible C-terminal arm plus insertion loop that rearrange upon substrate binding, features that distinguish it from human TrxR and provide selective inhibitor-binding surfaces (PMID:22889878, PMID:23845423). These structural and mechanistic distinctions underlie its validation as an antimalarial drug target, with Mannich-base mechanism-based inhibitors that alkylate the C-terminal cysteine pair and act selectively on the parasite enzyme in vivo (PMID:14609342, PMID:16458512, PMID:23845423). The enzyme is dually localized to the cytosol and a second compartment via alternative translation initiation (PMID:21203490). In P. berghei, the TRXR ortholog is dispensable throughout the life cycle, in contrast to its essentiality in P. falciparum blood stages (PMID:20852334).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Establishing which residues perform the core redox chemistry was needed to place TRXR mechanistically; mutagenesis identified the N-terminal disulfide and active-site base and assigned the enzyme to the high-Mr TrxR class.

    Evidence Site-directed mutagenesis, steady-state kinetics, and spectral analysis of recombinant enzyme from E. coli

    PMID:9368022

    Open questions at the time
    • Did not define how electrons reach the physiological substrate thioredoxin
    • No structural basis for the EH2 form
  2. 1998 High

    Because the N-terminal disulfide alone could not explain thioredoxin reduction, the C-terminal cysteines were tested and found specifically required for electron transfer to thioredoxin but not for low-Mr acceptor chemistry.

    Evidence Single, double, and deletion mutants assayed for DTNB reactivity versus thioredoxin reductase activity

    PMID:9563503

    Open questions at the time
    • Did not directly demonstrate the C-terminal cysteines act as kinetically competent electron acceptors
    • Did not assign individual roles to Cys535 vs Cys540
  3. 1999 High

    To prove the C-terminal cysteines are true catalytic intermediates rather than merely required, mixed-disulfide variants were reduced at wild-type-comparable rates, confirming an intramolecular dithiol-disulfide interchange relay.

    Evidence Reductive titrations of DTNB-modified C535A/C540A variants with stopped-flow rapid kinetics

    PMID:10074374

    Open questions at the time
    • Individual electrophile/nucleophile roles of the two cysteines remained undefined
    • Intersubunit geometry not yet established
  4. 2000 High

    The spatial organization of the two redox centers was unknown; co-expression of complementary mutants showed the enzyme is a head-to-tail homodimer with active sites spanning both subunits.

    Evidence Co-expression of differentially tagged wild-type and mutant subunits in E. coli, heterodimer purification, and activity assays

    PMID:11022050

    Open questions at the time
    • Cooperativity between active sites was implied but not fully quantified
    • No atomic structure of the dimer interface at this stage
  5. 2001 Medium

    Defining the physiological substrate specificity clarified TRXR's cellular role; kinetics with the cognate PfTrx showed markedly higher catalytic efficiency and lower Km than for model thioredoxins.

    Evidence Recombinant enzyme steady-state kinetics comparing cognate PfTrx and E. coli thioredoxin in coupled assays (with earlier characterization in 11013257)

    PMID:11013257 PMID:11223129

    Open questions at the time
    • Substrate preference measured in vitro only, single lab
    • Did not address which cellular thioredoxin pools are accessible in vivo
  6. 2002 High

    Whether TRXR is required for parasite survival determined its drug-target value; failed knockout with complementation rescue established essentiality in erythrocytic stages.

    Evidence Gene knockout by homologous recombination, co-transfection rescue, and multiple molecular verifications in P. falciparum

    PMID:12004069

    Open questions at the time
    • Essentiality shown for blood stage only
    • Which downstream redox function is limiting for survival not defined
  7. 2006 High

    The chemical basis of catalysis was refined by showing His509 acts with Glu514 as an acid-base dyad driving both half-reactions and the dithiol-disulfide interchange.

    Evidence Site-directed mutagenesis of His509Gln and Glu514Ala with steady-state and stopped-flow kinetics and anaerobic spectral titrations

    PMID:16950793

    Open questions at the time
    • Precise protonation states during turnover not directly observed
    • Structural context of the dyad not yet crystallographically resolved
  8. 2003 High

    Testing druggability, heme and Mannich-base compounds were shown to inhibit TRXR, with Mannich bases alkylating specifically the C-terminal cysteine pair as mechanism-based inhibitors.

    Evidence FP-agarose pull-down and Ki determination for hemin; mechanism-based inhibitor studies with thiol-conjugation models and charge-transfer monitoring

    PMID:12748176 PMID:14609342

    Open questions at the time
    • Cellular relevance of heme inhibition not established in these studies
    • Selectivity over human TrxR not yet quantified
  9. 2006 Medium

    Selective inhibition over the human enzyme was required for therapeutic value; Mannich-base derivatives showed uncompetitive, parasite-selective inhibition and antiplasmodial activity.

    Evidence Enzyme inhibition IC50/mode determination for PfTrxR versus hTrxR and antiplasmodial assay against K1 strain

    PMID:16458512

    Open questions at the time
    • Target engagement in vivo not yet demonstrated
    • Single lab, single study
  10. 2010 Medium

    The subcellular distribution and organismal requirement were addressed: dual cytosolic/second-compartment localization arises via alternative translation initiation, and the P. berghei ortholog is dispensable across the life cycle.

    Evidence Systematic localization mapping (GFP fusions/fractionation) in P. falciparum; gene targeting and life-cycle phenotyping in P. berghei

    PMID:20852334 PMID:21203490

    Open questions at the time
    • The additional non-cytosolic compartment is not precisely identified
    • Basis for the P. falciparum/P. berghei essentiality divergence unexplained
  11. 2011 Medium

    Post-translational regulation was explored; TRXR was identified as an S-glutathionylation target in the parasite glutathionylome.

    Evidence Enzymatic deglutathionylation, biotin-maleimide affinity purification, and proteomic MS in P. falciparum

    PMID:21595565

    Open questions at the time
    • Functional consequence of glutathionylation for TRXR activity not demonstrated
    • Modified residues not mapped
  12. 2012 High

    A structural basis for selective inhibition was needed; the crystal structure revealed a Plasmodium-specific dimer interface offering a non-competitive inhibitor-binding site absent in human and other apicomplexan enzymes.

    Evidence X-ray crystallography of recombinant PfTrxR at 2.9 Å

    PMID:22889878

    Open questions at the time
    • Substrate-bound conformation not resolved in this structure
    • Inhibitor complexes at the interface not directly captured
  13. 2013 High

    How TRXR engages its substrate was resolved by the co-crystal structure, showing the flexible C-terminal arm and Plasmodium-specific insertion loop rearrange on thioredoxin binding, with inhibitors validated to act on the enzyme in vivo.

    Evidence X-ray crystallography of the TrxR–Trx1 complex, structure-guided mutagenesis, and cell-biological inhibitor assays

    PMID:23845423

    Open questions at the time
    • Full catalytic-cycle conformational dynamics not directly visualized
    • Mechanism of the second-compartment role not addressed
  14. 2014 High

    The chemical logic of the unusual C-terminal redox center was dissected, showing the 20-membered type II disulfide ring geometry and Gly541 hydrogen bond are essential and that the native Cys-based center operates via electrophilic activation.

    Evidence Protein semisynthesis (Sec, homocysteine incorporation) and mutagenesis with kinetics on cognate and non-cognate substrates

    PMID:24400600

    Open questions at the time
    • Individual redox roles of Cys535 vs Cys540 not yet separated
    • Ring dynamics during catalysis inferred, not observed
  15. 2018 High

    The individual catalytic roles within the C-terminal ring were finally assigned: Cys535 is the electrophile/leaving group and Cys540 the nucleophile in the interchange with the N-terminal dithiol.

    Evidence Selenocysteine 'seleno effect' substitution at individual C-terminal residues in truncated and full-length semisynthetic enzymes

    PMID:29485860

    Open questions at the time
    • Transition-state structure not directly determined
    • Contribution of the intersubunit geometry to these roles not isolated
  16. 2017 Medium

    TRXR's place in the wider redox network was defined by substrate accessibility, showing certain thioredoxin isoforms are poor TRXR substrates and are instead served by the glutathione/glutaredoxin system.

    Evidence In vitro cross-reactivity and activity assays between glutathione-system components and thioredoxin isoforms

    PMID:28479253

    Open questions at the time
    • Physiological significance of the complementation in vivo not established
    • Compartment-specific access not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved why TRXR is essential in P. falciparum but dispensable in P. berghei, what the second (non-cytosolic) localization compartment is and what TRXR does there, and whether S-glutathionylation functionally regulates the enzyme.
  • Species divergence in essentiality unexplained
  • Identity and function of the second localization compartment unknown
  • Functional impact of glutathionylation undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
FERRIPROTOPORPHYRIN IX / HEMIN (INHIBITOR, KI ~1 ΜM) [#7]P. FALCIPARUM THIOREDOXIN 1 (COGNATE SUBSTRATE) [#4, #5, #15]
Complex memberships
Homodimer with intersubunit active sites (head-to-tail arrangement) [#3, #14]TRXR–thioredoxin 1 substrate complex [#15]

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Site-directed mutagenesis of P. falciparum TRXR identified Cys88 and Cys93 as the essential redox-active disulfide (mutation to Ala or Ser caused total loss of enzymatic activity), and His509 as the active-site base (mutation to Gln or Ala caused 95–97% loss of activity). Spectral analysis revealed a 550-nm absorption band upon reduction, characteristic of the EH2 form seen in glutathione reductase and lipoamide dehydrogenase, confirming TRXR belongs to the large (high-Mr) class of TrxRs. Site-directed mutagenesis, steady-state kinetic analysis, spectral analysis of recombinant protein expressed in E. coli The Journal of biological chemistry High 9368022
1998 The C-terminal cysteines Cys535 and Cys540 of P. falciparum TRXR are crucially involved in thioredoxin reduction. Single mutants (C535A, C540A), double mutant (C535A/C540A), and a 9-amino-acid C-terminal deletion mutant all lost thioredoxin reductase activity while retaining reactivity with DTNB, indicating the C-terminal cysteine pair is required for substrate coordination and/or electron transfer to thioredoxin rather than for FAD-proximal redox chemistry. Site-directed mutagenesis (single, double, deletion mutants), DTNB reactivity assay, thioredoxin reductase activity assay FEBS letters High 9563503
1999 Reductive titrations of C535A and C540A single-mutant TRXR enzymes modified with DTNB to form C-terminal mixed disulfides showed that each C-terminal cysteine, when presented as a TNB mixed disulfide mimicking the proposed disulfide acceptor, is reduced at a rate comparable to the wild-type turnover number. This directly demonstrates that the C-terminal cysteines participate as electron acceptors in catalysis via intramolecular dithiol-disulfide interchange with the nascent N-terminal dithiol. Reductive titrations of mixed-disulfide enzyme variants, stopped-flow rapid kinetics, spectrophotometric TNB release assay Biochemistry High 10074374
2000 Co-expression of differentially tagged wild-type and mutant TRXR subunits in E. coli demonstrated that the enzyme forms head-to-tail homodimers with intersubunit active sites: co-expression of the double mutant PfTrxRC88AC535A with wild-type yielded an inactive heterodimer, showing that each active site spans both subunits (N-terminal Cys88/Cys93 from one subunit, C-terminal Cys535/Cys540 from the other). Data also implied cooperative interaction between the two active sites. Co-expression of tagged wild-type and mutant proteins in E. coli, affinity chromatography purification of heterodimers, activity assay The Journal of biological chemistry High 11022050
2000 Recombinant P. falciparum TRXR (PfTrxR) was stably expressed by silent mutagenesis and biochemically characterized. P. falciparum thioredoxin (PfTrx) is a substrate for TRXR with Km = 10.4 µM and kcat = 3100 min⁻¹; notably PfTrx is a better substrate for human TrxR (Km = 2 µM, kcat = 3300 min⁻¹). Reduced PfTrx was shown to reduce GSSG with a rate constant k2 = 0.039 µM⁻¹ min⁻¹, approximately 5-fold higher than thioredoxins from human, Drosophila, or E. coli, suggesting that the TRXR/Trx system can support GSSG reduction in glutathione reductase-deficient conditions. Recombinant protein expression (silent mutagenesis), steady-state kinetics, coupled enzyme assays The Journal of biological chemistry High 11013257
2001 Steady-state kinetic analyses with recombinant TRXR and its natural substrate PfTrx gave Km values of 0.8–2.1 µM for PfTrx, approximately 250-fold lower than for the model substrate E. coli thioredoxin; with similar kcat values this represents ≥250-fold higher catalytic efficiency for the cognate substrate. Recombinant protein expression, steady-state kinetics in coupled assay systems Molecular and biochemical parasitology Medium 11223129
2002 Gene knockout attempts showed it was impossible to generate P. falciparum parasites with a disrupted trxR gene, establishing that TRXR is essential for erythrocytic stage survival. Co-transfection with a knockout construct plus a trxR coding sequence under the calmodulin promoter rescued viability despite disruption of the endogenous locus; co-transfectants were viable and overexpressed TRXR as confirmed by Northern and Western blot. PFGE and FIGE confirmed targeting was confined to chromosome 9 trxR locus. Gene knockout by homologous recombination, co-transfection rescue experiment, Southern blot, PFGE/FIGE, Northern blot, Western blot The Journal of biological chemistry High 12004069
2003 Ferriprotoporphyrin IX (FP/hemin) inhibits P. falciparum TRXR with a Ki of 1 µM, identified by enzyme activity assay with FP-immobilized agarose pull-down and kinetic analysis, indicating TRXR is a heme-interacting protein susceptible to inhibition by toxic heme released during hemoglobin degradation. FP-agarose pull-down, enzyme activity inhibition assay (Ki determination) The Journal of biological chemistry Medium 12748176
2003 Mannich bases act as mechanism-based (bisalkylating) inhibitors of P. falciparum TRXR. Mechanistic studies showed that the C-terminal Cys535'/Cys540' pair—not the N-terminal Cys88/Cys93 pair—is the site of alkylation; alkylated TRXR loses thioredoxin reductase activity but retains ability to reduce low-Mr electron acceptors via the unmodified N-terminal thiols. The charge-transfer complex between Cys88 thiolate and FAD was used spectroscopically to monitor N-terminal thiol status. Mechanism-based inhibitor synthesis, thiol conjugation model studies, spectrophotometric charge-transfer complex monitoring, enzyme activity assays with defined substrates Biochemistry High 14609342
2006 Steady-state kinetics, anaerobic static titrations, and rapid kinetics of wild-type TRXR and His509Gln / Glu514Ala variants established that the His509-Glu514 dyad acts as the acid-base catalyst. His509Gln retained only 0.5% wild-type activity with severely reduced rate constants in both reductive and oxidative half-reactions and no thiolate-flavin charge-transfer complex. Glu514Ala retained 7% activity and was shown to be involved in dithiol-disulfide interchange between the Cys88/Cys93 and Cys535/Cys540 pairs; Glu514 greatly enhances His509's catalytic role. Site-directed mutagenesis, steady-state kinetics, anaerobic spectral titrations, stopped-flow rapid kinetics The Journal of biological chemistry High 16950793
2006 Three Mannich-base-derived compounds showed selective uncompetitive inhibition of P. falciparum TRXR relative to human TrxR (IC50 values 0.5–2 µM for PfTrxR vs. 4–140 µM for hTrxR). Mechanistic characterization of the most specific inhibitor (compound 7) via thiol conjugation model demonstrated alkylation mechanism. All three compounds showed antiplasmodial activity against chloroquine-resistant K1 strain. Enzyme inhibition assays (IC50, kinetic mode determination), thiol conjugation model for mechanism, in vitro antiplasmodial assay Bioorganic & medicinal chemistry letters Medium 16458512
2010 Alternative translation initiation (ATI) is used by P. falciparum to achieve dual subcellular localization of TRXR: the enzyme is targeted to both the cytosol and an additional compartment through use of an alternative start codon, as determined by systematic subcellular localization mapping of redox proteins. Subcellular localization mapping of antioxidant/redox proteins by systematic study including GFP fusions and fractionation PLoS pathogens Medium 21203490
2010 In P. berghei, thioredoxin reductase gene was successfully disrupted by gene targeting, demonstrating that TRXR (the P. berghei ortholog) is dispensable for blood-stage proliferation and for the entire parasite life cycle, in contrast to the essential role shown in P. falciparum. Glutathione reductase, but not TRXR, was found essential for extracellular development in the insect vector. Gene targeting/knockout in P. berghei, phenotypic analysis across life cycle stages The Journal of biological chemistry High 20852334
2011 P. falciparum TRXR was identified as a target of protein S-glutathionylation in a proteomic screen of the Plasmodium glutathionylome, using enzymatic deglutathionylation, biotin-maleimide affinity purification, and mass spectrometry. This establishes TRXR as a potential redox-regulated target of this post-translational modification in the parasite. Enzymatic deglutathionylation, affinity purification of biotin-maleimide-tagged proteins, proteomic MS identification Antioxidants & redox signaling Medium 21595565
2012 Crystal structure of recombinant P. falciparum TRXR was solved at 2.9 Å resolution, revealing that the dimer interface differs substantially from human TrxR and offers a selective binding site for non-competitive inhibitors. The Plasmodium-specific dimer interface architecture is conserved among Plasmodium species but absent in other Apicomplexa and mammals. X-ray crystallography (2.9 Å resolution) of recombinant PfTrxR Biochemical and biophysical research communications High 22889878
2013 Crystal structure of the P. falciparum TRXR–thioredoxin 1 complex was solved, revealing that the flexible C-terminal arm and a Plasmodium-specific insertion loop of TRXR are rearranged upon complex formation, suggesting the C-terminal arm undergoes conformational change during catalysis. Key differences from human TrxR in thioredoxin binding mode and the C-terminal arm conformation were identified. Cell biological experiments confirmed that specific TRXR inhibitors with antimalarial activity act on the parasite enzyme in vivo. X-ray crystallography of TrxR–Trx complex, structure-guided mutagenesis of substrate-binding and intersubunit-cavity residues, cell biological assays with specific inhibitors Journal of molecular biology High 23845423
2014 Semisynthesis and site-directed mutagenesis of the C-terminal redox motif (G534CGGGKCG541, type II) of P. falciparum TRXR established: (i) deletion of Gly541 reduces activity ~50-fold by disrupting a stabilizing hydrogen bond in the β-turn-β motif; (ii) alterations of the 20-membered disulfide ring by deletion or substitution impair catalysis; (iii) replacement of Cys with homocysteine (semisynthesis) reduced activity by disrupting ring geometry; (iv) a chimeric TRXR bearing the type I GCCG sequence had 500-fold less activity, while the GCUG (selenocysteine) chimera had higher activity, supporting an 'electrophilic activation' mechanism for the native Cys-based type II center. Site-directed mutagenesis, protein semisynthesis (incorporation of selenocysteine and homocysteine), steady-state kinetic assays with cognate and non-cognate substrates Biochemistry High 24400600
2018 Using the 'seleno effect' approach (Sec substitution for Cys), it was established that Cys535 acts as an electrophile/leaving group (C535U substitution decreased activity ~9-fold) while Cys540 acts as the nucleophile attacking the N-terminal dithiol (C540U substitution increased activity ~1.5-fold) in the thiol-disulfide exchange step between the N-terminal and C-terminal redox centers of P. falciparum TRXR. Full-length semisynthetic enzymes confirmed these roles. Protein semisynthesis (selenocysteine substitution at individual C-terminal residues), activity assays with truncated and full-length semisynthetic enzymes Biochemistry High 29485860
2017 The glutathione system (via glutaredoxin) can reduce thioredoxin-like protein 1 and thioredoxin 2, which are either poor substrates for TRXR or lack access to TRXR, providing functional complementation between the two redox systems. This cross-talk was demonstrated biochemically, placing TRXR within a broader redox network where its substrate specificity limits access to certain thioredoxin isoforms. In vitro biochemical cross-reactivity assays between glutathione system components and thioredoxin isoforms, activity measurements Biochemical and biophysical research communications Medium 28479253

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Thioredoxin reductase as a pathophysiological factor and drug target. European journal of biochemistry 289 11012663
2000 Thioredoxin reductase two modes of catalysis have evolved. European journal of biochemistry 266 11012662
2004 Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Molecular microbiology 242 15387810
2000 The thioredoxin system of the malaria parasite Plasmodium falciparum. Glutathione reduction revisited. The Journal of biological chemistry 201 11013257
2003 Thiol-based redox metabolism of protozoan parasites. Trends in parasitology 174 12855383
2010 Compartmentation of redox metabolism in malaria parasites. PLoS pathogens 122 21203490
2008 New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications. FEBS letters 121 18294965
2012 Thioredoxin and glutathione systems in Plasmodium falciparum. International journal of medical microbiology : IJMM 100 22939033
2002 The diversity and evolution of thioredoxin reductase: new perspectives. Trends in parasitology 99 12379950
2002 Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages. The Journal of biological chemistry 91 12004069
2011 Protein S-glutathionylation in malaria parasites. Antioxidants & redox signaling 87 21595565
2006 The thiol-based redox networks of pathogens: unexploited targets in the search for new drugs. BioFactors (Oxford, England) 73 17012768
2006 Thioredoxin networks in the malarial parasite Plasmodium falciparum. Antioxidants & redox signaling 72 16910770
2002 The thioredoxin system of Plasmodium falciparum and other parasites. Cellular and molecular life sciences : CMLS 64 12169015
2002 Methylseleninate is a substrate rather than an inhibitor of mammalian thioredoxin reductase. Implications for the antitumor effects of selenium. The Journal of biological chemistry 61 11782468
2006 Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. Bioorganic & medicinal chemistry letters 60 16458512
2003 Identification and characterization of heme-interacting proteins in the malaria parasite, Plasmodium falciparum. The Journal of biological chemistry 58 12748176
2003 Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity. Biochemistry 57 14609342
1996 Recombinant putative glutathione reductase of Plasmodium falciparum exhibits thioredoxin reductase activity. Molecular and biochemical parasitology 56 8892299
1997 Identification and characterization of the functional amino acids at the active site of the large thioredoxin reductase from Plasmodium falciparum. The Journal of biological chemistry 54 9368022
1999 Thioredoxin reductase from Plasmodium falciparum: evidence for interaction between the C-terminal cysteine residues and the active site disulfide-dithiol. Biochemistry 53 10074374
2007 The relationship of the redox potentials of thioredoxin and thioredoxin reductase from Drosophila melanogaster to the enzymatic mechanism: reduced thioredoxin is the reductant of glutathione in Drosophila. Biochemistry 50 17550271
1998 The role of the C-terminus for catalysis of the large thioredoxin reductase from Plasmodium falciparum. FEBS letters 43 9563503
2001 The malaria parasite Plasmodium falciparum possesses a functional thioredoxin system. Molecular and biochemical parasitology 42 11223129
2008 Compounds structurally related to ellagic acid show improved antiplasmodial activity. Antimicrobial agents and chemotherapy 37 19015351
2010 Molecular genetics evidence for the in vivo roles of the two major NADPH-dependent disulfide reductases in the malaria parasite. The Journal of biological chemistry 35 20852334
2013 Crystal structure of the Plasmodium falciparum thioredoxin reductase-thioredoxin complex. Journal of molecular biology 33 23845423
2002 Thioredoxin, thioredoxin reductase, and thioredoxin peroxidase of malaria parasite Plasmodium falciparum. Methods in enzymology 32 11898428
2014 Why is mammalian thioredoxin reductase 1 so dependent upon the use of selenium? Biochemistry 31 24393022
2011 Screening of natural compounds for ligands to PfTrxR by ultrafiltration and LC-MS based binding assay. Journal of pharmaceutical and biomedical analysis 29 21353756
2012 Crystal structure of Plasmodium falciparum thioredoxin reductase, a validated drug target. Biochemical and biophysical research communications 26 22889878
2013 Lipid peroxidation and antioxidant enzymes activity in Plasmodium vivax malaria patients evolving with cholestatic jaundice. Malaria journal 25 24020374
2006 Eosin B as a novel antimalarial agent for drug-resistant Plasmodium falciparum. Antimicrobial agents and chemotherapy 24 16940112
2014 A new enniatin antibiotic from the endophyte Fusarium tricinctum Corda. The Journal of antibiotics 23 25315756
2014 The redox systems of Plasmodium falciparum and Plasmodium vivax: comparison, in silico analyses and inhibitor studies. Current medicinal chemistry 22 24304272
2020 Gold(iii) bis(dithiolene) complexes: from molecular conductors to prospective anticancer, antimicrobial and antiplasmodial agents. Metallomics : integrated biometal science 21 32391537
2003 Thioredoxin reductase and glutathione synthesis in Plasmodium falciparum. Redox report : communications in free radical research 21 14962359
2000 Intersubunit interactions in Plasmodium falciparum thioredoxin reductase. The Journal of biological chemistry 21 11022050
2006 Identification of acid-base catalytic residues of high-Mr thioredoxin reductase from Plasmodium falciparum. The Journal of biological chemistry 20 16950793
2003 Double-drug development against antioxidant enzymes from Plasmodium falciparum. Redox report : communications in free radical research 20 14962365
1999 Synthesis of 5,5'-dithiobis(2-nitrobenzamides) as alternative substrates for trypanothione reductase and thioredoxin reductase: a microtiter colorimetric assay for inhibitor screening. Analytical biochemistry 20 10036154
2018 Gold(i) phosphine compounds as parasite attenuating agents for malaria vaccine and drug development. Metallomics : integrated biometal science 18 29465117
2015 Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery. Molecules (Basel, Switzerland) 18 26111176
2012 Discovery and biochemical characterization of Plasmodium thioredoxin reductase inhibitors from an antimalarial set. Biochemistry 17 22612231
2008 Differential inhibition of high and low Mr thioredoxin reductases of parasites by organotelluriums supports the concept that low Mr thioredoxin reductases are good drug targets. Parasitology 17 18980703
2017 Glutathione and thioredoxin systems of the malaria parasite Plasmodium falciparum: Partners in crime? Biochemical and biophysical research communications 16 28479253
2014 A mechanistic investigation of the C-terminal redox motif of thioredoxin reductase from Plasmodium falciparum. Biochemistry 16 24400600
2014 Determination of antiplasmodial activity and binding affinity of curcumin and demethoxycurcumin towards PfTrxR. Natural product research 13 24443991
2009 Structural model of the Plasmodium falciparum thioredoxin reductase:a novel target for antimalarial drugs. Journal of vector borne diseases 11 19724080
2016 Preliminary LC-MS Based Screening for Inhibitors of Plasmodium falciparum Thioredoxin Reductase (PfTrxR) among a Set of Antimalarials from the Malaria Box. Molecules (Basel, Switzerland) 10 27043496
2021 A proteomic glimpse into the effect of antimalarial drugs on Plasmodium falciparum proteome towards highlighting possible therapeutic targets. Pathogens and disease 9 33202000
2015 Uncovering new structural insights for antimalarial activity from cost-effective aculeatin-like derivatives. Organic & biomolecular chemistry 9 25519040
2022 Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes. International journal of molecular sciences 8 35806151
2018 A "Seleno Effect" Differentiates the Roles of Redox Active Cysteine Residues in Plasmodium falciparum Thioredoxin Reductase. Biochemistry 8 29485860
2011 Identification of oleamide in Guatteria recurvisepala by LC/MS-based Plasmodium falciparum thioredoxin reductase ligand binding method. Planta medica 8 21567357
2009 Glutathione reductase and thioredoxin reductase: novel antioxidant enzymes from Plasmodium berghei. The Korean journal of parasitology 8 19967095
2018 Gain of function conferred by selenocysteine: catalytic enhancement of one-electron transfer reactions by thioredoxin reductase. Protein science : a publication of the Protein Society 7 30052295
2013 Characterization of PfTrxR inhibitors using antimalarial assays and in silico techniques. Chemistry Central journal 7 24209891
2015 Effects of cyclin-dependent kinase inhibitor Purvalanol B application on protein expression and developmental progression in intra-erythrocytic Plasmodium falciparum parasites. Malaria journal 5 25879664
2012 Development of liquid chromatography/mass spectrometry based screening assay for PfTrxR inhibitors using relative quantitation of intact thioredoxin. Rapid communications in mass spectrometry : RCM 5 22847705
2013 Determination of antiplasmodial activity and binding affinity of selected natural products towards PfTrxR and PfGR. Natural product communications 4 24079187
2026 Free Radical Formation in the Reactions of Redox-Active Drugs and Xenobiotics with Mitochondrial Flavoenzymes. Biomolecules 0 42352277