Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The reagent sym-triazine trichloride is used as a bifunctional reagent to generate RNA-protein cross-links within intact ribosomal subunits from E. coli. The reaction takes place in a stepwise manner, involving substitution of one chlorine atom at 12 degrees and pH 8, and substitution of the second at 40 degrees and pH 6. The cross-linked proteins are analysed by two-dimensional electrophoresis, and the existence of a stable cross-linkage is demonstrated by isolating protein-oligonucleotide complexes from 32P-labelled subunits. The proteins cross-linked are S3 and S4 in the 30S subunit, and L2 in the large subunit, together with smaller amounts of other proteins. The reagent should prove useful in topographical studies of the E. coli ribosome as it is a rigid molecule and generates very short cross-links.
Mol Gen Genet 1979 Jan 05
PMID:The use of sym-triazine trichloride in RNA-protein cross-linking studies with Escherichia coli ribosomal subunits. 37 42

1. Total-body neutron-activation analysis in vivo was carried out in 11 hypertensive subjects to measure simultaneously the total body content of sodium, chlorine, calcium, phosphorus and nitrogen. 2. There was a highly significant correlation between total body sodium measured by activation analysis and total exchangeable sodium measured by a standard isotope-dilution technique (r = 0.92, P less than 0.001). Exchangeable sodium averaged 80.3% of total body sodium. 3. The measured values of chlorine, calcium, phosphorus and nitrogen were similar to those for healthy subjects reported by others. 4. Activation analysis in vivo appears promising as an additional tool for investigating sodium metabolism in hypertension, as it is the only method available for determining the total body content of this element. The radiation dose (1 rem) is sufficiently low to permit repeated measurements in the same subject.
Clin Sci Mol Med 1978 Feb
PMID:Concurrent estimation of total body and exchangeable body sodium in hypertension. 41 89

Xenopus oocyte expression of the recently cloned gamma-aminobutyric acid (GABA) rho 1 receptor subunit cDNA yields a pharmacologic profile characteristic of the GABAc responses described by Johnston [Benzodiazepine/GABA Receptors and Chloride Channels. Receptor Biochemistry and Methodology (R. W. Olsen and J. C. Venter, eds), Vol. 5. Alan R. Liss, New York, 57-71 (1986)] and the responses to retinal mRNA recently reported in the Xenopus expression system [Proc. Natl. Acad. Sci. USA 88:4318-4322 (1991)]. A rationale for defining GABA rho 1 as forming a GABAc receptor is discussed.
Mol Pharmacol 1992 Apr
PMID:gamma-Aminobutyric acid A or C receptor? gamma-Aminobutyric acid rho 1 receptor RNA induces bicuculline-, barbiturate-, and benzodiazepine-insensitive gamma-aminobutyric acid responses in Xenopus oocytes. 131 44

The glycine site on the N-methyl-D-aspartate (NMDA) subtype of receptors for the excitatory neurotransmitter glutamate is a potential target for the development of neuroprotective drugs. We report here two chemical series of glycine site antagonists derived from kynurenic acid (KYNA), with greatly improved potency and selectivity. Disubstitution with chlorine or bromine in the 5- and 7-positions of KYNA increased affinity for [3H]glycine binding sites in rat cortex/hippocampus P2 membranes, with a parallel increase of potency for antagonism of NMDA-evoked responses in the rat cortical wedge preparation. The optimal compound was 5-I,7-Cl-KYNA, with an IC50 for [3H]glycine binding of 29 nM and an apparent Kb in the cortical wedge preparation of 0.41 microM. Reduction of the right-hand ring of 5,7-diCl-KYNA reduced affinity by 10-fold, but this was restored by substitution in the 4-position with the trans-phenylamide and further improved in the trans-benzylamide. The optimal compound was the transphenylurea (L-689,560), with an IC50 of 7.4 nM and an apparent Kb of 0.13 microM. Both series of compounds displayed a high degree of selectivity for the glycine site, having IC50 values of greater than 10 microM versus radioligand binding to the glutamate recognition sites of NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate receptors and the strychnine-sensitive glycine receptor. Selectivity versus AMPA receptor-mediated responses was also apparent in the rat cortical wedge and in patch-clamp recordings of cortical neurons in culture. Experiments using [3H]dizocilpine (MK-801) binding indicated that 5,7-diBr-KYNA, 5,7-diCl-KYNA, 5-I,7-Cl-KYNA, and L-689,560 all behaved as full antagonists and were competitive with glycine. Patch-clamp recordings of cortical neurons in culture also indicated that NMDA-induced currents were antagonized by competition for the glycine site, and gave no evidence for partial agonist activity. pKi values for 5,7-diBr-KYNA and L-689,560 in these experiments were 7.2 and 7.98, respectively, similar to the affinities of these compounds in the glycine binding assay. The high affinity and selectivity of these new derivatives make them useful tools to investigate the function of the glycine site on the NMDA receptor.
Mol Pharmacol 1992 May
PMID:Kynurenic acid analogues with improved affinity and selectivity for the glycine site on the N-methyl-D-aspartate receptor from rat brain. 137 17

The crystal and molecular structures of estramustine and two of its analogues have been determined by X-ray crystallographic techniques (a total of three different compounds). The compounds studied are estramustine [1,3,5(10)-estratriene-3,17 beta-diol-3-N,N-bis(2'- chloroethyl)carbamate] and its monohydrate, estromustine [17-oxo-1,3,5(10)-estratriene-3-yl-N,N-bis(2'-chloroethyl)carbamate], and 17-oxo-5-androsten-3 beta-yl-N,N-bis(2'-chloroethyl)carbamate. Three views of estramustine were obtained from the study of its two crystal forms. The main structural features found are as follows: (a) the geometries of the steroid moieties are closely similar to those of the parent steroids, (b) the bonds around the nitrogen atom of the nitrogen mustard grouping lie approximately in a plane in each structure, (c) the plane through the carbon atoms of the steroid A-ring lies approximately perpendicular to the plane through the carbamate atoms in each structure, (d) the carbonyl C-O of the carbamate points to the alpha side of the steroid moiety in each structure, and (e) one chlorine atom of the nitrogen mustard grouping makes a close contact [3.13 A], in each structure, to the nitrogen atom. Hydrogen bonding to the carbamate appears to occur from the alpha side of the steroid; there is no hydrogen bonding to the nitrogen atom of the carbamate group. These structural data provide some steric explanations for the resistance of the carbamate to enzymatic hydrolysis. The long in vivo half-life of the intact estramustine molecule is a result of this stability. This is responsible for the absence of alkylating ability and the propensity of the drug to bind microtubule-associated proteins and express an antimitotic mechanism of action.
Mol Pharmacol 1992 Mar
PMID:Molecular conformation of estramustine and two analogues. 154 78

Two chlorinated hydroxylated furanones, 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone (MX) and 3,4-(dichloro)-5-hydroxy-2[5H]-furanone (MA), are bacterial mutagens and they are also byproducts of chlorine disinfection, and frequent contaminants of drinking water. In this work MX is shown to induce nuclear anomalies in the gastrointestinal tract of the B6C3F1 mouse. The other chlorohydroxy-furanone, MA, gives suggestive evidence of activity. In this bioassay MX was approximately equivalent in potency to epichlorohydrin (ECH) but was much less potent than methylnitrosourea (MNU). The latter two chemicals are confirmed rodent gastrointestinal tract carcinogens. The duodenum was the most sensitive tissue responding with both increased numbers of nuclear anomalies per mouse and increased incidence of animals presenting the nuclear aberrations 24 hr after a single oral dose of 0.37 mmol/kg-1 of MX. MA also induced a significant increase in duodenal nuclear anomalies, but only at the highest dose (0.46 mmol/kg-1). The proximal colon and forestomach responded to MX but not MA. This is the first study demonstrating that chlorohydroxyfuranones are capable of inducing nuclear toxicity in vivo. However, it is clear, for MX at least, that its potency in the gastrointestinal tract nuclear anomalies assay is not commensurate with its extreme bacterial mutagenicity. Since the gastrointestinal tract tissues are directly exposed to orally administered genotoxins, one possible explanation for the weak response observed in this study could be that mammalian cells can effectively detoxify chlorohydroxyfuranones.
Environ Mol Mutagen 1991
PMID:Induction of gastrointestinal tract nuclear anomalies in B6C3F1 mice by 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5H]-furanone and 3,4-(dichloro)-5-hydroxy-2[5H]-furanone, mutagenic byproducts of chlorine disinfection. 199 57

Chlorinated phenols, which are used primarily as wood preservatives and fungicides, are present in most air, water, and soil samples in industrialized areas as well as in the urine of most people. We have examined the ability of phenol and the 19 isomers of chlorophenol to induce DNA damage using the Microscreen prophage-induction assay in Escherichia coli. Seven of the isomers (2,3,4,-tri, 2,4,5-tri, 3,4,5-tri, 2,3,4,5-tetra, 2,3,6-tri, 2,4,6-tri, and pentachlorophenol) induced prophage lambda in the presence of S9, with the first three being approximately 10 times more potent than the last three. The more potent isomers have either one or no chlorine atom ortho to the OH group; whereas the less potent isomers have two chlorine atoms ortho to the OH group. Although none of the 20 compounds is mutagenic in Salmonella, the prophage-induction results agree with findings by others that most of these seven isomers are clastogenic, are associated with cancer and chromosomal aberrations in humans (pentachlorophenol), and are carcinogenic in rodents (2,4,6-tri and pentachlorophenol). A likely basis for the genotoxicity of the seven isomers involves the metabolism of the parent isomer to a chlorohydroquinone, which can form a chlorobenzosemiquinone in the presence of oxygen. These two metabolites can produce free radicals that can cause DNA strand breaks, resulting in prophage induction in E. coli or, possibly, the chromosomal aberrations/cancer associated with human exposure to chlorophenols.
Environ Mol Mutagen 1990
PMID:Induction of prophage lambda by chlorophenols. 213 84

The amidase activity of human alpha-thrombin has been studied in the pH range 5.5 to 10, and at four different chloride concentrations from 5 mM to 1 M. The Michaelis-Menten constant, Km, shows a bell-shaped dependence over the pH range studied, with a minimum around pH 8. The pH dependence of the catalytic constant, kcat, shows multiple inflection points especially at low (less than 0.1 M) chloride concentrations, thereby implicating the existence of multiple catalytic forms of the enzyme. A general linkage scheme is proposed for the analysis of the effect of protons on thrombin amidase activity, and experimental data have globally been analysed over the entire pH range in terms of such a scheme. Four proton-linked ionizable groups seem to be involved in the control of thrombin amidase activity. Two of these groups change their pK value upon substrate binding to the enzyme and account for the pH dependence of Km. All four groups control the catalytic activity of the enzyme which decreases with increasing protonation. Chloride has little effect on Km, while kcat changes significantly at pH less than 8. This effect is due to an increased enzymatic activity of the highly protonated intermediates at high chloride concentrations, as well as to the pK shift of two proton-linked ionizable groups.
J Mol Biol 1990 Dec 20
PMID:Effect of protons on the amidase activity of human alpha-thrombin. Analysis in terms of a general linkage scheme. 226 57

Rats orally given radioactive Clebopride [[14C]CP; N-(1'-benzyl-4'-piperidyl)-2-[14C]methoxy-4-amino-5-chlorobenzamide++ +], an antiulcer agent, excreted a novel type of ornithine (Orn)-GSH double conjugate in the bile as a major metabolite [( 14C]BMCP), corresponding to 18% of the dose. The present study provides the first evidence for Orn conjugation of a xenobiotic in mammals and demonstrates that the structure of the radioactive conjugate differs fundamentally from those known in birds and reptiles. The structure of the biliary metabolite, [14C]BMCP, purified to homogeneity by silica gel thin layer and reverse phase high pressure liquid chromatography, was elucidated as S-[2-ornithylamino-4-[14C]methoxy-5-(1'-methyl-4'-piperidylamin o) carboxyphenyl]glutathione, based mainly on the following facts: 1) BMCP showed a protonated molecular ion (M + H)+ peak at m/z 683 in the secondary ion mass spectrum and 2) [14C]BMCP afforded Orn, glutamic acid, glycine, S-(2-amino-4-[14C]methoxy-5-carboxyphenyl)cysteine [( 14C]AMCC), and 1-methyl-4-aminopiperidine (MAP) quantitatively, in an equal molar ratio, by complete hydrolysis with peptidase. Thus, BMCP was a metabolite with three enzymatically hydrolyzable amide bonds in addition to the one existing originally in the parent structure of the drug, which produces MAP by peptic digestion. Of the three additional amide bonds of BMCP, one was a novel type of bond formed by condensation of the alpha-carboxylic acid group of Orn with the primary aromatic amino group of the drug and the other two were in the S-glutathionyl residue, substituted for the chlorine atom vicinal to the Orn-conjugating primary amino group in the aromatic ring and affording glutamic acid, glycine, and the S-cysteine conjugate AMCC by hydrolysis of BMCP with the peptidase. Substitution of a methyl group for the benzyl group at the piperidine ring nitrogen atom, leading to the formation of MAP by peptic digestion, also occurred during metabolism of CP to BMCP.
Mol Pharmacol 1990 Jun
PMID:Novel type of ornithine-glutathione double conjugate excreted as a major metabolite into the bile of rats administered clebopride. 235 8

Following a brief introduction of cellular response to stimulation comprising leukocyte activation, three major areas are discussed: (1) the neutrophil oxidase; (2) myeloperoxidase (MPO)-dependent oxidative microbicidal reactions; and (3) MPO-independent oxidative reactions. Topics included in section (A) are current views on the activation mechanism, redox composition, structural and topographic organization of the oxidase, and its respiratory products. In section (B), emphasis is placed on recent research on cidal mechanisms of HOCl, including the oxidative biochemistry of active chlorine compounds, identification of sites of lesions in bacteria, and attendant metabolic consequences. In section (C), we review the (bio)chemistry of H2O2 and .OH microbicidal reactions, with particular attention being given to addressing the controversial issue of probe methods to identify .OH radical and critical assessment of the recent proposal that MPO-independent killing arises from site-specific metal-catalyzed Fenton-type chemistry.
Crit Rev Biochem Mol Biol 1989
PMID:Leukocytic oxygen activation and microbicidal oxidative toxins. 254 10


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