Disease relevance of ECs4890

• The Escherichia coli OxyR transcription factor senses H2O2 and is activated through the formation of an intramolecular disulfide bond [1].
• Escherichia coli OxyR modulation of bacteriophage Mu mom expression in dam+ cells can be attributed to its ability to bind hemimethylated Pmom promoter DNA [2].
• Salmonella can enhance its resistance to oxidants through the induction of specific genetic pathways controlled by SoxRS, OxyR, sigma(S), sigma(E), SlyA, and RecA [3].
• Lack of expression of the global regulator OxyR in Haemophilus influenzae has a profound effect on growth phenotype [4].
• OxyR regulon mutants should be useful for identifying other determinants of INH resistance in both E. coli and Mycobacterium tuberculosis and for finding new INH-like drugs [5].

High impact information on ECs4890

• Using the transcription factor OxyR as a model, we have generated, in vitro, several stable, posttranslational modifications of the single regulatory thiol (SH), including S-NO, S-OH, and S-SG, and shown that each occurs in vivo [6].
• Here we report that certain S-nitrosothiols (RSNOs) impose what we term a "nitrosative stress" to E. coli, evidenced by lowering of intracellular thiol and the transcriptional activation of OxyR by S-nitrosylation [7].
• The results suggest that direct oxidation of the OxyR protein brings about a conformational change by which OxyR transduces an oxidative stress signal to RNA polymerase [8].
• Both the oxidized and the reduced forms of the OxyR protein are capable of binding to three diverse sequences upstream of OxyR-regulated promoters, but the interactions of the two forms of OxyR with the promoter regions are different [8].
• A DeltaoxyRS mutant strain of E. coli was significantly more susceptible than the parent strain to neutrophil-mediated killing, which suggests that OxyR-regulated gene products contribute a measure of resistance to neutrophil antimicrobial systems [9].

Chemical compound and disease context of ECs4890

• Redox-sensitive transcription factors such as the E. coli OxyR and S. cerevisiae Yap1, are activated by conformational changes that stem from the post-translational modification of reactive protein thiols [10].
• Overproduction of OxyR in Streptomyces lividans conferred resistance against cumene hydroperoxide and H2O2 [11].
• Pretreatment with HOCl conferred resistance to H2O2 in an OxyR-independent manner, suggesting a specific adaptive response to HOCl. fur mutants, which have an intracellular iron overload, were more sensitive to HOCl, supporting the generation of hydroxyl radicals upon HOCl exposure via a Fenton-type reaction [12].
• LysR proteins have been shown to regulate urease in Klebsiella aerogenes (NAC), and catalase in Escherichia coli (OxyR), which offers the intracellular bacterium protection from phagolysosome damage [13].
• To elucidate the role of OxyR in Pseudomonas putida KT2442, the oxyR1 mutation that caused the upregulation of ahpC in a toluene-resistant variant strain was introduced, because no null mutants in oxyR were isolated [14].

Biological context of ECs4890

• Genes regulated by the oxidant sensing transcription factor OxyR were among those strongly induced upon phagocytosis by normal, but not oxidase-deficient, neutrophils [9].
• The utility of this collection covering about 30% of the transcriptional units was tested by analyzing individual fusions representative of heat shock, SOS, OxyR, SoxRS, and cya/crp stress-responsive regulons [15].
• One such suppressor strain, FA113, grows almost as rapidly as the wild type in the absence of reductant, exhibits slightly faster kinetics of disulfide bond formation, and has fully induced activity of the transcriptional activator, OxyR [16].
• Methylation interference assays on two OxyR-binding sites showed that OxyR contacts its recognition sequences predominantly at positions of degenerate homology [17].
• OxyR protein purified in its oxidized form was found to bind four of its non-homologous, functional DNA-binding sites with over 10(6)-fold higher affinity than random DNA sequences [17].

Associations of ECs4890 with chemical compounds

• An important and provocative study of the modification of thiols in the transcription factor OxyR recently extended this hypothesis [18].
• Mass spectrometric analysis of activated OxyR revealed thioesterification of the critical regulatory cysteine, Cys-199, to an avicin fragment comprising the outer monoterpene side chain [19].
• Key regulators of the adaptive responses in this organism are the SoxRS and OxyR transcription factors, which induce the expression of antioxidant activities in response to O2*- and H2O2 stress, respectively [20].
• The OxyR-regulated alkyl hydroperoxide reductase encoded by ahpFC did not detectably affect H2O2 or catalase activity levels [21].
• Experiments using strains expressing mutant OxyR proteins with Cys to Ser single amino acids substitutions confirmed that the disulfide bond is formed between the Cys-199 and -208 [22].

Analytical, diagnostic and therapeutic context of ECs4890

• The results of immunoblotting experiments demonstrated that the level of OxyR protein exhibits the same biphasic expression [23].
• In this study, I demonstrated by SDS-PAGE under non-reducing conditions that an intramolecular disulfide bond is formed in OxyR upon exposure of the cells to hydrogen peroxide in vivo [22].
• The DNA microarray measurements allowed the identification of several new OxyR-activated genes, including the hemH heme biosynthetic gene; the six-gene suf operon, which may participate in Fe-S cluster assembly or repair; and four genes of unknown function [24].
• Using site-directed mutagenesis, we found that one cysteine residue (C-199) is critical for the redox sensitivity of OxyR, and a C-199-->S mutation appears to lock the OxyR protein in the reduced form [25].
• Northern blot hybridization, promoter-lacZ fusion, and enzyme assay experiments revealed that its expression, unlike in Escherichia coli, is OxyR-independent and constitutive upon oxidative stress conditions [26].

References