Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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During the reductive process in the tissues, the aerobes generate a number of oxidants. Unless these oxidants are reduced, oxidative damage and cell death would occur. Oxidation of plasma membrane lipids leads to autocatalytic chain reactions which eventually alter the permeability of the cell. The role of oxidative damage in the pathophysiology of diabetic complications and ischemic reperfusion injury of myocardium, especially the changes in the channel activity which may lead to arrhythmia have been studied. Hyperglycemia activates aldose reductase which could efficiently reduce glucose to sorbitol in the presence of NADPH. Since NADPH is also aldose required by glutathione reductase for reducing oxidants, its diversion would lead to membrane lipid oxidation and permeability changes which are probably responsible for diabetic complications such as cataractogenesis, retinopathy, neuropathy etc. Antioxidants such as butylated hydroxy toluene (BHT) and also reductase inhibitors prevent or delay some of these complications. By using patch-clamp technique in isolated frog myocytes, we have shown that hydroxy radicals generated by ferrous sulfate and ascorbate as well as lipid peroxides such as t-butyl hydroperoxide facilitate the entry of Na+ by oxidizing Na+-channels. Increased intracellular Na+ leads to an increase in Na+/Ca2+ exchange. The increased Na+ concentration by itself may produce electrical disturbance which would result in arrhythmia. Increased Ca2+ may affect proteases and may help in the conversion of xanthine dehydrogenase to xanthine oxidase, consequently increased production of super oxide radicals. Increased membrane lipid peroxidation and other oxygen free-radical associated membrane damage in myocytes has been demonstrated.
Mol Cell Biochem
PMID:The effect of oxidants on biomembranes and cellular metabolism. 251 41

Toluene degrading (xyl) genes on a Pseudomonas TOL plasmid pWW0 are located within a 39-kb DNA portion. The 56-kb region including these xyl genes and its 17-kb derivative with a deletion of the internal 39-kb portion transposed to various sites on target replicons such as pACYC184 and R388 in Escherichia coli recA strains. Thus the 56- and 17-kb regions were designated Tn4651 and Tn4652, respectively. Genetic analysis of Tn4652 demonstrated that its transposition occurs by a two-step process, namely, cointegrate formation and its subsequent resolution. The presence in cis of DNA sequences of no more than 150 bp at both ends of Tn4652 was prerequisite for cointegrate formation, and this step was mediated by a trans-acting factor, transposase, which was encoded in a 3.0-kb segment at one end of the transposon. Cointegrate resolution took place site-specifically within a 200-bp fragment, which was situated 10 kb away from the transposase gene. Based on the stability of cointegrates formed by various mini-Tn4652 derivatives, it was shown that the cointegrate resolution requires two trans-acting factors encoded within 1.0- and 1.2-kb fragments that encompass the recombination site involved in the resolution.
Mol Gen Genet 1987 Dec
PMID:Genetic analysis of a transposon carrying toluene degrading genes on a TOL plasmid pWW0. 283 Apr 57

A Pseudomonas TOL plasmid pWW0 possesses toluene degradative pathway (xyl) genes. Unstable maintenance of a pWW0 derivative in Escherichia coli allowed us to identify two transposable elements each carrying all the xyl genes. One element corresponded to a 56 kb transposon, Tn4651, which we had previously characterized. The other element newly identified in this study was 70 kb long, and this element, designated Tn4653, completely included Tn4651. Genetic analysis of Tn4653 demonstrated that its transposition involves two steps, i.e. cointegrate formation and its subsequent resolution. The former step required a trans-acting factor, transposase, which was encoded in a 3.0 kb fragment at one end of Tn4653, and the latter step was inferred to be mediated by the factors necessary for resolution of the Tn4651-mediated cointegrate. The transposase functions were not interchangeable between the two transposons.
Mol Gen Genet 1988 Jul
PMID:Identification and characterization of Tn4653, a transposon covering the toluene transposon Tn4651 on TOL plasmid pWW0. 285 12

Twenty-seven chemicals previously tested in rodent carcinogenicity assays were tested for induction of chromosomal aberrations (ABS) and sister chromatid exchanges (SCE) in Chinese hamster ovary (CHO) cells as part of a larger analysis of the correlation between results of in vitro genetic toxicity assays and carcinogenicity bioassays. Chemicals were tested up to toxic doses with and without exogenous metabolic activation. Seventeen of the chemicals tested were carcinogens; only two of these were negative for both ABS and SCE. Of the eight noncarcinogens tested, four were negative for both endpoints (ABS and SCE) and four gave a positive response for at least one endpoint. Of the remaining two chemicals, one, diallyl phthalate, gave an equivocal response in the bioassay and a positive response in these CHO cell cytogenetics tests. The other chemical, 2,4-toluene diisocyanate, was tested for carcinogenicity as a mixture with the 2,6-isomer; the mixture was carcinogenic, but the cytogenetic test results for the 2,4-isomer were negative. Only six of the 27 chemicals tested produced an effect in one endpoint alone; the other 21 were either positive or negative for both ABS and SCE. Only one of the 27 chemicals tested required S9 for a positive response in the SCE test; two chemicals required S9 for a positive result in the ABS test. Experiments with unsynchronized CHO cells demonstrated that mean SCE frequency increased with increasing culture time, and this may have been a factor in the positive results obtained for five chemicals in the SCE test under conditions of delayed harvest.
Environ Mol Mutagen 1989
PMID:Chromosome aberration and sister chromatid exchange tests in Chinese hamster ovary cells in vitro. III. Results with 27 chemicals. 291 52

A subcellular fraction enriched 12 times in glycosomes (NAD+-linked alpha-glycerophosphate dehydrogenase) and devoid of detectable contamination from other subcellular components, was prepared from bloodstream Trypanosoma rhodesiense. Using a method employing exposure to toluene as a means of studying normally latent glycosomal enzymes, and phospholipase A2 as a membrane probe, the association of adenylate kinase and alpha-glycerophosphate dehydrogenase with the glycosome was studied. The normally latent glycerophosphate dehydrogenase (NAD+ linked), it is proposed, is an intraglycosomal enzyme having no membrane association, but bound to the core by weak ionic linkages. As such it is possible to release the enzyme from permeable (toluene treated) glycosomes using Cl-, with a resulting 4-fold increase in the Km for dihydroxyacetone phosphate. The presence of Cl- also stimulates an increase in specific activity, but this is observed before any release of enzyme. In contrast adenylate kinase, a non-latent glycosomal enzyme, is clearly membrane associated, the use of phospholipase A2 revealing an absolute dependence on phospholipid for activity. Restoration of activity appears to specifically require phosphatidyl choline and to be co-operative in nature (nH = 1.56). It is proposed that adenylate kinase is an integral glycosomal membrane enzyme, probably affecting the control of intra-glycosomal ADP/ATP levels.
Mol Biochem Parasitol 1985 Feb
PMID:The presence of alpha-glycerophosphate dehydrogenase (NAD+-linked) and adenylate kinase as core and integral membrane enzymes respectively in the glycosomes of Trypanosoma rhodesiense. 298 83

The mass density of protein crystals can be measured in Ficoll gradients as a function of hydrostatic pressure. Carbon tetrachloride-toluene mixtures provide convenient density markers, and the compressibility of these standards is reported. Measurements on tetragonal crystals of hen egg-white lysozyme yielded densities at room temperature of 1.2367(+/- 0.0010) g cm-3 at 1 atm and 1.2586(+/- 0.0017) g cm-3 at 1000 atm (1 atm = 101,325 Pa). When combined with the unit cell dimensions at these two pressures these values lead to an estimated compression (fractional change in volume) of the crystal solvent at 1000 atm of 0.0369(+/- 0.0054). This value is comparable to that of a 0.7 M solution of NaCl. From an approximate estimate of the Donnan effect for the crystal in the 1.4 M-NaCl mother liquor, the crystal solvent contains 0.8 M-Na+ and 2.5 M-Cl-. It is concluded that the compressibility of solvent in lysozyme crystals is, within experimental error, the same as bulk solvent and does not exhibit the dramatically altered compressibility expected of an ice or glass-like solid. The crystallographically observable water sites, 151 at 1 atm and 163 at 1000 atm, showed a tendency to increase the number of hydrogen bonds made to other water sites at the expense of hydrogen bonds made to protein. The explanation for this phenomenon is presently unknown. Water sites that occur in both structures tend to have comparable temperature factors and show some tendency to follow the pressure-induced changes in protein atom positions. The compression expected for the water molecules themselves is too small to be observable at the resolution of the X-ray data collected in this study.
J Mol Biol 1988 Mar 20
PMID:Effect of hydrostatic pressure on the solvent in crystals of hen egg-white lysozyme. 337 35

Seventy-two chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector (Mutat Res 44:269-278, 1975) and Clive et al. (Mutat Res 59:61-108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p-benzoquinone dioxime, benzyl acetate, 2-biphenylamine HCl, bis(2-chloro-1-methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2-chloroethanol, chlorothalonil, cytarabine.HCl, p,p'-DDE, diazinon, 2,6-dichloro-p-phenylenediamine, N,N-diethylthiourea, diglycidylresorcinol ether, 2,4-dimethoxy aniline.HCl, disperse yellow 3, endosulfan, 1,2-epoxyhexadecane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4'-methylenedianiline.2 HCl, methyl viologen, nickel sulfate.6H2O, 4,4'-oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6-tetrachloro-4-nitro-anisole, 1,1,1,2-tetrachloroethane, trichlorfon, 2,4,6-trichlorophenol, 2,4,5-trimethoxybenzaldehyde, 1,1,3-trimethyl-2-thiourea, 1-vinyl-3-cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2-biphenylamine.HCl, 2-chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2-tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11-aminoudecanoic acid, boric acid, 5-chloro-o-toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2-ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4-sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4-dichlorobenzene, phenol, succinic acid-2,2-dimethyl hydrazide, and toluene.
Environ Mol Mutagen 1988
PMID:Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. 338 42

TOL plasmid pWWO of Pseudomonas putida contains two operons that specify a pathway for the degradation of aromatic hydrocarbons. The 'upper' operon encodes enzymes for the oxidation of toluene to benzoate and xylenes to toluates, whereas the meta-cleavage operon specifies the further oxidation of benzoate and toluates. Transcription of the upper pathway operon is positively regulated by the XylR protein, which is activated by toluene/xylenes and their alcohol catabolic products, in combination with the NtrA protein, a sigma factor. Expression of the meta-operon is positively controlled by the XylS protein which is activated by meta-pathway substrates, and is independent of NtrA protein. Expression of the meta pathway is also induced by toluene/xylene-activated XylR protein via a cascade regulatory system in which this protein in combination with NtrA protein stimulates transcription from the xylS gene promoter. Hyper-production of XylS protein in turn provokes high level expression of the meta-operon, which is independent of meta-pathway substrates. The two promoters, which are activated by the XylR and NtrA proteins, the upper pathway promoter and the xylS gene promoter, exhibit three regions of homology centred at -12(5'-TTGCATG-3'), -24(5'-TGGCPuT-3') and -45(5'-TAAAATAAGPuPuCGPuTC-3'), with respect to their principal transcription initiation points. The possible physiological significance of activated XylR-protein-induced expression of the meta-operon through amplification of XylS protein levels is considered.
Mol Microbiol 1987 Nov
PMID:Regulatory circuits controlling transcription of TOL plasmid operon encoding meta-cleavage pathway for degradation of alkylbenzoates by Pseudomonas. 344 61

TOL plasmid pWW0 and plasmid NAH7 encode catabolic enzymes required for oxidative degradation of toluene and naphthalene, respectively. The gene order of the catabolic operon of NAH7 for salicylate oxidation was determined to be: promoter--nahG (the structural gene for salicylate hydroxylase)--nahH (catechol 2.3-dioxygenase)--nahI (hydroxymuconic semialdehyde dehydrogenase)--nahN (hydroxymuconic semialdehyde hydrolase)--nahL (2-oxopent-4-enoate hydratase). This order is identical to that of the isofunctional genes of TOL plasmid pWW0. The complete nucleotide sequence of nahH was determined and compared with that of xylE, the isofunctional gene of TOL plasmid pWW0. There were 20% and 16% differences in their nucleotide and amino acid sequences, respectively. The homology between the NAH7 and TOL pWW0 plasmids ends upstream of the Shine-Dalgarno sequences of nahH and xylE, but the homology continues downstream of these genes. This observation suggested that genes for the catechol oxidative enzymes of NAH7 and TOL pWW0 were derived from a common ancestral sequence which was transferred as a discrete segment of DNA between plasmids.
Mol Gen Genet 1987 Dec
PMID:Evolutionary relationships between catabolic pathways for aromatics: conservation of gene order and nucleotide sequences of catechol oxidation genes of pWW0 and NAH7 plasmids. 348 21

The in vitro metabolism of phenelzine (2-phenylethylhydrazine) by phenobarbital-pretreated rat liver microsomes yields ethylbenzene, 2-phenylethanol, 2-phenylacetaldehyde, benzaldehyde, benzylalcohol, and toluene as metabolites. Isotopic studies demonstrate that the oxygen atom of 2-phenylethanol derives from molecular oxygen and that this alcohol is not produced by reduction of 2-phenylacetaldehyde. The rates of destruction of cytochrome P-450, accumulation of spin-trapped 2-phenylethyl radicals, and formation of ethylbenzene and 2-phenylethanol are the same for [1,1-2H]-2-phenylethylhydrazine as for the undeuterated substrate. Small primary isotope effects are observed, however, for the formation of 2-phenylacetaldehyde (kH/kD greater than 1) and benzaldehyde (kH/kD less than 1). Synthetic 2-phenylethylhydroperoxide is converted by liver microsomes to the same alcohol and aldehyde metabolites. The results indicate that the metabolism of phenelzine by rat liver microsomes proceeds primarily via the 2-phenylethyl radical.
Mol Pharmacol 1987 Feb
PMID:Free radical pathways in the in vitro hepatic metabolism of phenelzine. 380 96


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