Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.8.1.12 (trypanothione reductase)
 355 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trypanothione reductase is an FAD-dependent disulfide oxidoreductase which catalyses the reduction of trypanothione using NADPH as co-factor. The enzyme is unique to protozoan parasites from the genera Trypanosoma and Leishmania and is an important target for the design of improved antitrypanocidal drugs. We present details of the structure of trypanothione reductase from Crithidia fasciculata solved by molecular replacement, using human glutathione reductase as a search model, and refined to an R factor of 16.1% with data between 8.0 and 2.6 A resolution. The model comprises two subunits (one containing 487 residues, the other 486), an FAD prosthetic group, plus 392 solvent molecules. The last four C-terminal residues are not seen in either subunit and the density is poor for the N-terminal residue of subunit B. The model has a root-mean-square deviation from ideality of 0.016 A for bond lengths and 3.2 degrees for bond angles. Each subunit was independently refined in the latter stages of the analysis but the subunits remain similar as indicated by the root-mean-square deviation of 0.35 A for C(alpha) atoms. Trypanothione reductase has 36% sequence identity with human glutathione reductase and the root-mean-square deviation between the 462 C(alpha) atoms in the secondary structural units common to the two proteins is 1.1 A. However, there are large differences in the loop regions and significant shifts in the orientation of the four domains within each subunit. Domain II, which binds the dinucleotide co-factor, and domain IV, which forms the interface between the two subunits, are both rotated by approximately 5 degrees with respect to domain I, which binds the FAD moiety, when compared with glutathione reductase. Crystals of trypanothione reductase have been soaked in the dinucleotide co-factor NADPH and N(1)-glutathionylspermidine disulfide substrate and the structure of the resulting complex determined at 2.8 A resolution. Strong density is observed for the adenosine end of the co-factor which forms many charged interactions with the protein though the density for the nicotinamide moiety is more diffuse. The mode of binding indicates that NADP is bound to the enzyme in a similar conformation to that observed with human glutathione reductase.
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PMID:Structure of trypanothione reductase from Crithidia fasciculata at 2.6 A resolution; enzyme-NADP interactions at 2.8 A resolution. 1529 52

In an approach to discover new inhibitors of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease, a virtual high-throughput screening was performed. Two structurally new types of inhibitors emerged, the antimicrobial chlorhexidine {1,1'-hexamethylenebis[5-(4-chlorophenyl)biguanide]}, a linear competitive inhibitor (K(i) = 2 +/- 1 microM), and a piperidine derivative acting as mixed inhibitor (K(i) = 6.2 +/- 2 microM and K(i)' = 8.5 +/- 2 microM). Neither compound interferes with human glutathione reductase. Based on chlorhexidine, different series of compounds were synthesized and studied as inhibitors of T. cruzi trypanothione reductase. Most efficient derivatives were three bis(amidines) showing mixed type inhibition with K(i,slope) and K(i,int) values of 2-5 microM and 16-47 microM, respectively. Although these compounds did not exert an improved inhibitory potency compared to chlorhexidine, the change from competitive to mixed-type inhibition is advantageous, since substrate accumulation does not overcome inhibition. Remarkably, all three derivatives carried two copies of an identical 2-methoxy-4-methyl-1-(phenylmethoxy)benzene substituent.
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PMID:Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis. 1603 59

Glutathione is the major intracellular antioxidant thiol protecting mammalian cells against oxidative stress induced by oxygen- and nitrogen-derived reactive species. In trypanosomes and leishmanias, trypanothione plays a central role in parasite protection against mammalian host defence systems by recycling trypanothione disulphide by the enzyme trypanothione reductase. Although Kinetoplastida parasites lack glutathione reductase, they maintain significant levels of glutathione. The aim of this study was to use Leishmania donovani trypanothione reductase gene mutant clones and different Leishmania species to examine the role of these two individual thiol systems in the protection mechanism against S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a nitrogen-derived reactive species donor. We found that the resistance to SNAP of different species of Leishmania was inversely correlated with their glutathione concentration but not with their total low-molecular weight thiol content (about 0.18 nmol/10(7) parasites, regardless Leishmania species). The glutathione concentration in L. amazonensis, L. donovani, L. major, and L. braziliensis were 0.12, 0.10, 0.08, and 0.04 nmol/10(7) parasites, respectively. L. amazonensis, that have a higher level of glutathione, were less susceptible to SNAP (30 and 100 microM). The IC50 values of SNAP determined to L. amazonensis, L. donovani, L. major, and L. braziliensis were 207.8, 188.5, 160.9, and 83 microM, respectively. We also observed that L. donovani mutants carrying only one trypanothione reductase allele had a decreased capacity to survive (approximately 40%) in the presence of SNAP (30-150 microM). In conclusion, the present data suggest that both antioxidant systems, glutathione and trypanothione/trypanothione reductase, participate in protection of Leishmania against the toxic effect of nitrogen-derived reactive species.
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PMID:Glutathione and the redox control system trypanothione/trypanothione reductase are involved in the protection of Leishmania spp. against nitrosothiol-induced cytotoxicity. 1650 15

A series of polyaminoguanidines and polyaminobiguanides were synthesized and evaluated as potential antitrypanosomal agents. These analogues inhibit trypanothione reductase (TR) with IC50 values as low as 0.95 microM, but do not inhibit the closely related human enzyme glutathione reductase (GR). The most effective analogues, 7a, 7b and 8d, inhibited parasitic growth in vitro with IC50 values of 0.18, 0.09 and 0.18 microM, respectively. These agents represent a promising new class of potential antitrypanosomal agents.
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PMID:Novel alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity. 1661 95

This paper discusses the effects of two neuroleptic agents, chlorpromazine and trifluoperazine; three antimycotics, amphotericin B, ketoconazole and miconazole and four antibiotics, pentamidine, rifampicin, mepacrine and metronidazole on the NADPH-dependent disulfide reducing enzymes cystine reductase (CysR), glutathione reductase (GR) trypanothione reductase (TR) and a putative disulfide reductase for compound X in Acanthamoeba polyphaga from the human pathogens A. polyphaga and Naegleria fowleri. Against A. polyphaga, all nine drugs studied had the capacity to inhibit the putative disulfide reductase from the trophozoites at a concentration of 32microg/ml during a 24h incubation and they were: the neuroleptics trifluoperazine (100%) and chlorpromazine (96%), the antimycotics miconazole (89%) ketoconazole (81%) and amphotericin B, (53%) and the antibiotics pentamidine (89%), rifampicin (64%), mepacrine (57%) and metronidazole (14%). Only six of the nine drugs simultaneously inhibited CysR, GR and the putative disulfide reductase. In N. fowleri, the most potent inhibitors of trypanothione reductase were amphotericin B and miconazole which inhibited 100% at a concentration of 32microg/ml during the 24h incubation followed by the neuroleptics trifluoperazine (92%) and chlorpromazine (80%) and the antibiotic mepacrine (70%). All these also inhibited CysR and GR from the trophozoites other than mepacrine which inhibited only CysR and TR. Ketoconazole, rifampicin (which did not affect CysR), pentamidine and metronidazole had opposite effects since they did not inhibit but increased the amount of the three thiols.
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PMID:The effects by neuroleptics, antimycotics and antibiotics on disulfide reducing enzymes from the human pathogens Acanthamoeba polyphaga and Naegleria fowleri. 1680 88

A high-throughput screening campaign of a library of 100,000 lead-like compounds identified 2-iminobenzimidazoles as a novel class of trypanothione reductase inhibitors. These 2-iminobenzimidazoles display potent trypanocidal activity against Trypanosoma brucei rhodesiense, do not inhibit closely related human glutathione reductase and have low cytotoxicity against mammalian cells.
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PMID:Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening. 1719 85

Trypanosomatids, the causative agents of several tropical diseases, lack glutathione reductase and thioredoxin reductase but have a trypanothione reductase instead. The main low molecular weight thiols are trypanothione (N(1),N(8)-bis-(glutathionyl)spermidine) and glutathionyl-spermidine, but the parasites also contain free glutathione. To elucidate whether trypanosomes employ S-thiolation for regulatory or protection purposes, six recombinant parasite thiol redox proteins were studied by ESI-MS and MALDI-TOF-MS for their ability to form mixed disulfides with glutathione or glutathionylspermidine. Trypanosoma brucei mono-Cys-glutaredoxin 1 is specifically thiolated at Cys(181). Thiolation of this residue induced formation of an intramolecular disulfide bridge with the putative active site Cys(104). This contrasts with mono-Cys-glutaredoxins from other sources that have been reported to be glutathionylated at the active site cysteine. Both disulfide forms of the T. brucei protein were reduced by tryparedoxin and trypanothione, whereas glutathione cleaved only the protein disulfide. In the glutathione peroxidase-type tryparedoxin peroxidase III of T. brucei, either Cys(47) or Cys(95) became glutathionylated but not both residues in the same protein molecule. T. brucei thioredoxin contains a third cysteine (Cys(68)) in addition to the redox active dithiol/disulfide. Treatment of the reduced protein with GSSG caused glutathionylation of Cys(68), which did not affect its capacity to catalyze reduction of insulin disulfide. Reduced T. brucei tryparedoxin possesses only the redox active Cys(32)-Cys(35) couple, which upon reaction with GSSG formed a disulfide. Also glyoxalase II and Trypanosoma cruzi trypanothione reductase were not sensitive to thiolation at physiological GSSG concentrations.
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PMID:Glutathionylation of trypanosomal thiol redox proteins. 1724 9

Twenty-three heterocyclic compounds were evaluated for their potential as trypanothione reductase inhibitors. As a result, the harmaline, 10-thiaisoalloxazine, and aspidospermine frameworks were identified as the basis of inhibitors of Trypanosoma cruzi trypanothione reductase. Two new compounds showed moderately strong, linear competitive inhibition, namely N,N-dimethyl-N-[3-(7-methoxy-1-methyl-3,4-dihydro-9H-beta-carbolin-9-yl)propyl]amine (15) and 1,3-bis[3-(dimethylamino)propyl]-1,5-dihydro-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione (21), with K(i) values of 35.1+/-3.5microM and 26.9+/-1.9microM, respectively. Aspidospermine (25) inhibited T. cruzi TryR with a K(i) of 64.6+/-6.2microM. None of the compounds inhibited glutathione reductase. Their toxicity toward promastigotes of Leishmania amazonensis was assessed.
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PMID:The use of natural product scaffolds as leads in the search for trypanothione reductase inhibitors. 1855 92

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.
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PMID:Modeled structure of trypanothione reductase of Leishmania infantum. 1859 27

Trypanosomatids are pathogenic protozoa of the order Kinetoplastida. A unique feature of these parasitic protozoa is the presence of a unique dithiol trypanothione (N(1), N(8) -bis(glutathionyl)spermidine) and the flavoenzyme trypanothione reductase. This is in contrast to human and other eukaryotes, which contain ubiquitous glutathione/glutathione reductase system. An important function of thiols is to protect cells from toxic metabolic by-products such as methylglyoxal, a reactive 2-oxoaldehyde. Methylglyoxal is a mutagenic and a cytotoxic compound. The glyoxalase system is involved in the detoxification of methylglyoxal. The exceptionality of the glyoxalase enzyme in the parasitic protozoa is the dependence on the dithiol -trypanothione for detoxifying the toxic methylglyoxal. The detoxification process by the glyoxalase enzyme in eukaryotes and most other organisms is dependent on the tripeptide glutathione. The glyoxalase enzyme of trypanosomatids are also exceptional in a way that they use the divalent cation nickel as a cofactor like the glyoxalase enzyme of E. coli, whereas in eukaryotes the cofactor is zinc. This reflects that both the substrate as well as the cofactor of the kinetoplastids glyoxalase enzyme is distinct from that of the glyoxalase enzyme of eukaryotes. These differences reveal that the active site of the glyoxalase enzyme of the parasite and its mammalian counterpart are significantly different thereby proposing that the glyoxalase enzyme of the protozoan parasite can be a potential chemotherapeutic target.
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PMID:Glyoxalase pathway of trypanosomatid parasites: a promising chemotherapeutic target. 1899 8


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