Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Peroxiredoxins (Prxs) are thiol-dependent peroxidases that catalyze the detoxification of various peroxide substrates such as H2O2, peroxinitrite, and hydroperoxides, and control some signal transduction in eukaryotic cells. Prxs are found in all cellular organisms and represent an enormous superfamily. Recent genome sequencing projects and biochemical studies have identified a novel subfamily, the archaeal Prxs. Their primary sequences are similar to those of the 1-Cys Prxs, which use only one cysteine residue in catalysis, while their catalytic properties resemble those of the typical 2-Cys Prxs, which utilize two cysteine residues from adjacent monomers within a dimer in catalysis. We present here the X-ray crystal structure of an archaeal Prx from the aerobic hyperthermophilic crenarchaeon, Aeropyrum pernix K1, determined at 2.3 A resolution (Rwork of 17.8% and Rfree of 23.0%). The overall subunit arrangement of the A.pernix archaeal Prx is a toroid-shaped pentamer of homodimers, or an (alpha2)5 decamer, as observed in the previously reported crystal structures of decameric Prxs. The basic folding topology and the peroxidatic active site structure are essentially the same as those of the 1-Cys Prx, hORF6, except that the C-terminal extension of the A.pernix archaeal Prx forms a unique helix with its flanking loops. The thiol group of the peroxidatic cysteine C50 is overoxidized to sulfonic acid. Notably, the resolving cysteine C213 forms the intra-monomer disulfide bond with the third cysteine, C207, which should be a unique structural characteristic in the many archaeal Prxs that retain two conserved cysteine residues in the C-terminal region. The conformational flexibility near the intra-monomer disulfide linkage might be necessary for the dramatic structural rearrangements that occur in the catalytic cycle.
J Mol Biol 2005 Nov 25
PMID:Crystal structure of an archaeal peroxiredoxin from the aerobic hyperthermophilic crenarchaeon Aeropyrum pernix K1. 1621 69

We previously showed that thioredoxins are required for dithiothreitol (DTT) tolerance, suggesting they maintain redox homeostasis in response to both oxidative and reductive stress conditions. In this present study, we screened the complete set of viable deletion strains in Saccharomyces cerevisiae for sensitivity to DTT to identify cell functions involved in resistance to reductive stress. We identified 195 mutants, whose gene products are localized throughout the cell. DTT-sensitive mutants were distributed among most major biological processes, but they particularly affected gene expression, metabolism, and the secretory pathway. Strikingly, a mutant lacking TSA1, encoding a peroxiredoxin, showed a similar sensitivity to DTT as a thioredoxin mutant. Epistasis analysis indicated that thioredoxins function upstream of Tsa1 in providing tolerance to DTT. Our data show that the chaperone function of Tsa1, rather than its peroxidase function, is required for this activity. Cells lacking TSA1 were found to accumulate aggregated proteins, and this was exacerbated by exposure to DTT. Analysis of the protein aggregates revealed that they are predominantly composed of ribosomal proteins. Furthermore, aggregation was found to correlate with an inhibition of translation initiation. We propose that Tsa1 normally functions to chaperone misassembled ribosomal proteins, preventing the toxicity that arises from their aggregation.
Mol Biol Cell 2006 Jan
PMID:The thioredoxin system protects ribosomes against stress-induced aggregation. 1625 55

H(2)O(2) is a reactive oxygen species that has drawn much interest because of its role as a second messenger in receptor-mediated signaling. Mammalian 2-Cys peroxiredoxins have been shown to eliminate efficiently the H(2)O(2) generated in response to receptor stimulation. 2-Cys peroxiredoxins are members of a novel peroxidase family that catalyze the H(2)O(2) reduction reaction in the presence of thioredoxin, thioredoxin reductase and NADPH. Several lines of evidence suggest that 2-Cys peroxiredoxins have dual roles as regulators of the H(2)O(2) signal and as defenders of oxidative stress. In particular, 2-Cys peroxiredoxin appears to provide selective, specific and localized control of receptor-mediated signal transduction. Thus, the therapeutic potential of 2-Cys peroxiredoxins is clear for diseases, such as cancer and cardiovascular diseases, that involve reactive oxygen species.
Trends Mol Med 2005 Dec
PMID:2-Cys peroxiredoxin function in intracellular signal transduction: therapeutic implications. 1629 20

Heme oxygenase (HO)-1, the inducible isoform of the rate-limiting enzyme of heme degradation, and peroxiredoxin (Prx) I, a thioredoxin-dependent peroxidase, are multifunctional antioxidant stress proteins which are coordinately up-regulated by oxidative stress in cell cultures. HO-1 and Prx I exhibit a different hepatic cellular and subcellular localization. Here, a distinct expression pattern of the two genes was confirmed by in situ hybridization of normal rat liver. Moreover, expression of the HO-1 and Prx I genes was determined in a model of acutely damaged rat liver which was elicited by application of a single dose of carbon tetrachloride (CCl4). The mRNA levels of the HO-1 and Prx I genes were induced in whole livers of CCl4-treated rats with differential kinetics as determined by Northern blot analysis. While HO-1 mRNA was induced up to 48 hr, Prx I exhibited a maximum level of mRNA after 12 hr of treatment with CCl4. CCl4-dependent oxidative stress led to a focal increase of perivenous HO-1 positive liver cells with simultaneous loss of Prx I immunoreactivity. Taken together, the complementary hepatic gene expression pattern of HO-1 and Prx I in response to oxidative stress may suggest a functional interplay of these antioxidant genes.
Cell Mol Biol (Noisy-le-grand) 2005 Oct 03
PMID:Complementary regulation of heme oxygenase-1 and peroxiredoxin I gene expression by oxidative stress in the liver. 1630 69

Parasites of the Leishmania Viannia subgenus are major causative agents of mucocutaneous leishmaniasis (MCL), a disease characterised by parasite dissemination (metastasis) from the original cutaneous lesion to form debilitating secondary lesions in the nasopharyngeal mucosa. We employed a protein profiling approach to identify potential metastasis factors in laboratory clones of L. (V.) guyanensis with stable phenotypes ranging from highly metastatic (M+) through infrequently metastatic (M+/M-) to non-metastatic (M-). Comparison of the soluble proteomes of promastigotes by two-dimensional electrophoresis revealed two abundant protein spots specifically associated with M+ and M+/M- clones (Met2 and Met3) and two others exclusively expressed in M- parasites (Met1 and Met4). The association between clinical disease phenotype and differential expression of Met1-Met4 was less clear in L. Viannia strains from mucosal (M+) or cutaneous (M-) lesions of patients. Identification of Met1-Met4 by biological mass spectrometry (LC-ES-MS/MS) and bioinformatics revealed that M+ and M- clones express distinct acidic and neutral isoforms of both elongation factor-1 subunit beta (EF-1beta) and cytosolic tryparedoxin peroxidase (TXNPx). This interchange of isoforms may relate to the mechanisms by which the activities of EF-1beta and TXNPx are modulated, and/or differential post-translational modification of the gene product(s). The multiple metabolic functions of EF-1 and TXNPx support the plausibility of their participation in parasite survival and persistence and thereby, metastatic disease. Both polypeptides are active in resistance to chemical and oxidant stress, providing a basis for further elucidation of the importance of antioxidant defence in the pathogenesis underlying MCL.
Mol Biochem Parasitol 2006 Feb
PMID:Comparative protein profiling identifies elongation factor-1beta and tryparedoxin peroxidase as factors associated with metastasis in Leishmania guyanensis. 1632 36

Peroxiredoxins (Prxs) are a ubiquitous family of peroxidases widely distributed among prokaryotes and eukaryotes. Here, we report on the cloning and functional characterization of a cDNA designated PcPrx-1, encoding peroxiredoxin from the white-rot fungus Phanerochaete chrysosporium. The full-length PcPrx-1 cDNA (932 bp) contains an open reading frame of 200 amino acid residues with a molecular mass of 22.1 kDa. The deduced primary structure of PcPrx-1 polypeptide shows a high level of sequence identity to other recently identified 2-cys peroxiredoxins. The recombinant PcPrx-1 protein was expressed as a histidine fusion protein in Escherichia coli and purified with a Ni2+-column. The purified protein was shown to have a protective effect against plasmid DNA cleavage by reactive oxygen species. The PcPrx-1 protein displays the ability to remove H2O2 in a ferrithiocyanate system. The results of this study suggest that PcPrx-1 may play a protective role against oxidative stress in P. chrysosporium.
Cell Mol Biol Lett 2005
PMID:Molecular cloning and characterization of a peroxiredoxin from Phanerochaete chrysosporium. 1634 Dec 74

The proteins that are neosynthesized and secreted in the different regions of the human epididymis were determined by in vitro biosynthesis of epididymal tubules, and the luminal proteins were collected by microperfusion of each tubule. The preparations were analyzed by two-dimensional gel electrophoresis and the proteins were identified by mass spectrometry. Some of the major proteins identified corresponded to serum compounds such as albumin, transferrin and alpha-1-antitrypsin. The other proteins identified included lactotransferrin, clusterin, PEBP, NCP2/CTP/HE1, HE3, Crisp, actin, calmodulin, E12, PGDS, l-lactate dehydrogenase, malate dehydrogenase, carbonic anhydrase, triose phosphate isomerase, glutamyltransferase, glutathione S-transferase P, thioredoxin peroxidase, superoxide dismutase, cathepsin D and cystatin. Epididymal activity is highly regionalized in most species. However, in this study in humans, there were only minor changes in the major proteins secreted. It is suggested that this specificity might be related to the difference between species in the location of the epididymis where sperm become fertile.
Mol Cell Endocrinol 2006 May 16
PMID:Human epididymal secretome and proteome. 1643 Oct 15

Peroxiredoxins (Prxs) constitute a ubiquitous family of antioxidant enzymes involved in diverse cellular functions including cell proliferation and differentiation. To investigate the physiologic role of typical 2-Cys Prx in malaria parasites (TPx-1), we disrupted this gene in the rodent malaria parasite Plasmodium berghei (pbtpx-1). The gene-disrupted parasite (Prx KO) developed normally in mouse erythrocytes and multiplied at a rate similar to that of the parent strain (WT) during the experimental period. The normal growth rate was not altered after 10 passages, and the level of 8-hydroxy-2'-deoxyguanosine, which accumulates in the parasite genome during the cell cycle, was similar between Prx KO and WT. These results suggest that TPx-1 does not prevent parasite DNA oxidation, in contrast to mammalian Prx, and that it is not essential for asexual parasite growth in mouse erythrocytes. However, Prx KO produced up to 60% fewer gametocytes, sexual-stage parasites involved in the transition between the mammalian host and the mosquito, than WT did. The peak of gametocytemia was also delayed; however, the male/female ratio of gametocytes and the exflagellation activity of male gametocytes were normal. These results suggest that TPx-1 is required for normal gametocyte development but does not affect the male/female gametocyte ratio or male gametogenesis. Although the mechanism by which PbTPx-1 contributes to gametocyte development remains unknown, these findings suggest, for the first time, the involvement of Prx in the sexual development of the malaria parasite.
Mol Biochem Parasitol 2006 Jul
PMID:2-Cys Peroxiredoxin TPx-1 is involved in gametocyte development in Plasmodium berghei. 1659 67

The mitochondrial genome of trypanosomes, termed kinetoplast DNA (kDNA), contains thousands of minicircles and dozens of maxicircles topologically interlocked in a network. To identify proteins involved in network replication, we screened an inducible RNA interference-based genomic library for cells that lose kinetoplast DNA. In one cloned cell line with inducible kinetoplast DNA loss, we found that the RNA interference vector had aberrantly integrated into the genome resulting in overexpression of genes down-stream of the integration site (Motyka, S. A., Zhao, Z., Gull, K., and Englund, P. T. (2004) Mol. Biochem. Parasitol. 134, 163-167). We now report that the relevant overexpressed gene encodes a mitochondrial cytochrome b(5) reductase-like protein. This overexpression caused kDNA loss by oxidation/inactivation of the universal minicircle sequence-binding protein, which normally binds the minicircle replication origin and triggers replication. The rapid loss of maxicircles suggests that the universal minicircle sequence-binding protein might also control maxicircle replication. Several lines of evidence indicate that the cytochrome b(5) reductase-like protein controls the oxidization status of the universal minicircle sequence-binding protein via tryparedoxin, a mitochondrial redox protein. For example, overexpression of mitochondrial tryparedoxin peroxidase, which utilizes tryparedoxin, also caused oxidation of the universal minicircle sequence-binding protein and kDNA loss. Furthermore, the growth defect caused by overexpression of cytochrome b(5) reductase-like protein could be partially rescued by simultaneously overexpressing tryparedoxin.
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PMID:Overexpression of a cytochrome b5 reductase-like protein causes kinetoplast DNA loss in Trypanosoma brucei. 1669 Jun 8

The gastric pathogen Helicobacter pylori induces a strong inflammatory host response, yet the bacterium maintains long-term persistence in the host. H. pylori combats oxidative stress via a battery of diverse activities, some of which are unique or newly described. In addition to using the well-studied bacterial oxidative stress resistance enzymes superoxide dismutase and catalase, H. pylori depends on a family of peroxiredoxins (alkylhydroperoxide reductase, bacterioferritin co-migratory protein and a thiol-peroxidase) that function to detoxify organic peroxides. Newly described antioxidant proteins include a soluble NADPH quinone reductase (MdaB) and an iron sequestering protein (NapA) that has dual roles - host inflammation stimulation and minimizing reactive oxygen species production within H. pylori. An H. pylori arginase attenuates host inflammation, a thioredoxin required as a reductant for many oxidative stress enzymes is also a chaperon, and some novel properties of KatA and AhpC were discovered. To repair oxidative DNA damage, H. pylori uses an endonuclease (Nth), DNA recombination pathways and a newly described type of bacterial MutS2 that specifically recognizes 8-oxoguanine. A methionine sulphoxide reductase (Msr) plays a role in reducing the overall oxidized protein content of the cell, although it specifically targets oxidized Met residues. H. pylori possess few stress regulator proteins, but the key roles of a ferric uptake regulator (Fur) and a post-transcriptional regulator CsrA in antioxidant protein expression are described. The roles of all of these antioxidant systems have been addressed by a targeted mutant analysis approach and almost all are shown to be important in host colonization. The described antioxidant systems in H. pylori are expected to be relevant to many bacterial-associated diseases, as genes for most of the enzymes carrying out the newly described roles are present in a number of pathogenic bacteria.
Mol Microbiol 2006 Aug
PMID:The diverse antioxidant systems of Helicobacter pylori. 1687 43


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