Disease relevance of TSA1

• The roles of Cys-47 and Cys-170 in yeast TSA were investigated by replacing them individually with serine and expressing the mutant TSA proteins (RC47S and RC170S, respectively), as well as wild-type TSA (RWT), in Escherichia coli [1].
• We propose that Tsa1 normally functions to chaperone misassembled ribosomal proteins, preventing the toxicity that arises from their aggregation [2].
• Except for the AhpC protein identified in Salmonella typhimurium, none of the TSA-like proteins is associated with known cellular functions [3].
• Finally TSA medium supplemented with 0.05% yeast extract, 5% bovine blood, 0.01% DTT, 400 micrograms spectinomycin, and 250 micrograms/ml vancomycin, appeared to be optimal selective medium for intestinal Treponema sp. isolation [4].

Psychiatry related information on TSA1

• Antioxidant defense mechanisms: a new thiol-specific antioxidant enzyme [5].

High impact information on TSA1

• We have analyzed the functions of several pre-mRNA processing (PRP) proteins in yeast spliceosome formation [6].
• Defects in recombinational DNA double strand break repair, Rad6-mediated postreplicative repair, and DNA damage and replication checkpoints caused growth defects or lethality in the absence of Tsa1 [7].
• In addition, the mutator phenotypes caused by a tsa1 mutation were significantly aggravated by defects in Ogg1, mismatch repair, or checkpoints [7].
• Thiol-specific antioxidant (TSA) from yeast contains cysteine residues at amino acid positions 47 and 170 but is not associated with obvious redox cofactors [1].
• The antioxidant activity of the various TSA proteins was evaluated from their ability to protect glutamine synthetase against the dithiothreitol/Fe3+/O2 oxidation system [1].

Chemical compound and disease context of TSA1

• The role of TPx in the cellular defense against oxidative stress induced by singlet oxygen was investigated in Escherichia coli containing an expression vector with a yeast genomic DNA fragment that encodes TPx and mutant in which the catalytically essential amino acid cysteine (Cys-47) has been replaced with alanine by a site-directed mutagenesis [8].
• Its amino acid sequence was homologous to that of some prokaryotic and eukaryotic proteins such as thioredoxin peroxidase (formerly called thiol-specific antioxidant) in yeast and mammalian brains and the C22 component of alkyl hydroperoxide reductase in Salmonella typhimurium [9].

Biological context of TSA1

• This phenotype was rescued by the expression of either the TSA1 or TSA2 gene [10].
• Furthermore, the accumulation of cTPx II upon exposure to oxidative stress and during the postdiauxic shift suggests an important antioxidant role in stationary phase yeast cells [11].
• In addition to two yeast TPx isoforms (TSA I and TSA II/AHPC1) previously described, three additional TPx homologues were identified by analysis of the open reading frame data base for Saccharomyces cerevisiae [12].
• Therefore, with respect to substrate specificity, Ahp1p differs from Tsa1p and is similar to prokaryotic alkyl hydroperoxide reductase AhpC [13].
• In addition to two Yap1p response elements (YREs), TTACTAA and TTAGTAA, the presence of two stress response elements (STREs) (CCCCT) in the upstream sequence of cTPx II also suggests that Msn2p/Msn4p could control stress-induced expression of cTPx II [11].

Anatomical context of TSA1

• We report here that TSA1 confers resistance towards oxidative stress as well as is involved in the correct composition of hyphal cell walls [14].
• However, when the functional state of the mitochondria was compromised, the necessity of TSA1 in cell protection against this oxidant was much more evident [15].
• We have identified Tsa1p, a protein that is differentially localized to the cell wall of C. albicans in hyphal cells but remains in the cytosol and nucleus in yeast-form cells [14].
• Human T cell cyclophilin18 binds to thiol-specific antioxidant protein Aop1 and stimulates its activity [16].
• In contrast, S. cerevisiae spheroblasts lacking the TPx gene and/or treated with ATZ suffered a decrease in mitochondrial membrane potential, generated higher amounts of hydrogen peroxide and had decreased viability under these conditions [17].

Associations of TSA1 with chemical compounds

• Therefore, de novo synthesis and recycling of glutathione were increased in the tsa1Delta mutant to maintain the catalytic cycle of glutathione peroxidase reaction efficiently as a backup system for thioredoxin peroxidase [18].
• Unlike other TPx null mutants, cTPx I null mutant was hypersensitive to various oxidants except for 4-nitroquinoline N-oxide [12].
• Cells lacking TSA1 were found to accumulate aggregated proteins, and this was exacerbated by exposure to DTT [2].
• TPx exists as a dimer of identical 25-kDa subunits that contain 2 cysteine residues, Cys47 and Cys170 [19].
• This 25-kDa protein acts as a peroxidase but requires a NADPH-dependent thioredoxin system or a thiol-containing intermediate, and was thus named thioredoxin peroxidase (TPx) [20].

Physical interactions of TSA1

• The primary regulator of the PHR1 damage response is a 39-bp sequence called URS(PHR1) which is the binding site for a protein(s) that constitutes the damage-responsive repressor PRP [21].

Enzymatic interactions of TSA1

• Conversely, loss of Srx1 prevents the reduction of oxidized Tpx1 and prolongs the inhibition of Pap1 activation [22].

Other interactions of TSA1

• Here we report on the functional characterization of yeast tsa2Delta mutants and the comparison of TSA1 with TSA2 [10].
• Similar to yeast Tsa1p, Ahp1p forms a disulfide-linked homodimer upon oxidation and in vivo requires the presence of the thioredoxin system but not of glutathione to perform its antioxidant protective function [13].
• Taken together, these results suggest that cTPx II is a target of Msn2p/Msn4p transcription factors under negative control of the Ras-protein kinase A and target of rapamycin signaling pathways [11].
• It has been suggested that both transcription-activating proteins, Yap1p and Skn7p, regulate the transcription of cTPx II upon exposure to oxidative stress [11].
• Thus, Tsa1, a ubiquitous thioredoxin peroxidase, is required for the activation of Yap1 in yeast strain Y700, which is derived from W303 [23].

Analytical, diagnostic and therapeutic context of TSA1

• Analysis of the transcriptional activity of site-directed mutagenesis of the putative STREs (STRE1 and STRE2) and YREs (TRE1 and YRE2) in terms of the activity of a lacZ reporter gene under control of the cTPx II promoter indicates that STRE2 acts as a principal binding element essential for transactivation of the cTPx II promoter [11].
• We investigated the mechanism by which TSA protects biomolecules from oxidative damage caused by the thiol-containing oxidation system using the spin trapping method with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) [24].
• Southern blot analysis of petite yeast DNA, studies with protein synthesis inhibitors, and protein immunoblot analyses of cytosolic and mitochondrial proteins suggest that TSA is a cytosolic protein encoded by nuclear DNA (chromosome XIII) [25].
• The selective interaction of the dimer form of cTPx II (the oxidized form) with SFH2p was also confirmed by glutathione S-transferase pull-down and immunoprecipitation assays [26].
• Radiolabeled orotidine 5'-phosphate (OMP), generated in situ from [7-(14)C]-orotate and alpha-d-5-phoshorylribose 1-diphosphate (PRPP), binds tightly enough to OPRTase (a dimer composed of identical subunits) that the complex survives gel-filtration chromatography [27].

References