Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We demonstrate that [3H]captopril selectively labels angiotensin converting enzyme (EC 3.14.15.1) (ACE) and employ this technique to probe enzyme-inhibitor interactions. [3H]Captopril binding sites copurify with ACE activity from rat lung or rat brain. At each stage of the purification the Vmax/Bmax ratio, or kcat is 17,000 min-1 with hippuryl-L-histidyl-L-leucine as substrate. The specificity of [3H]captopril binding is apparent in the similar pharmacologic profile of inhibition in crude and pure enzyme preparations. Furthermore, binding sites and enzyme activity comigrate in gel filtration and sucrose gradient sedimentation experiments. Equilibrium analysis of [3H]captopril binding to purified ACE reveals a Bmax of 6 nmol/mg of protein (KD = 2 nM), demonstrating the presence of one inhibitor binding site per polypeptide chain. The kinetics of [3H]captopril binding are characterized by monophasic association and dissociation rate constants of 0.026 nM-1 min-1 and 0.034 min-1, respectively. The affinity of ACE for both [3H] captopril and enalaprilat is greater at 37 degrees than at 0 degree, demonstrating that these interactions are entropically driven, perhaps by an isomerization of the enzyme molecule. The ionic requirements for [3H]captopril binding and substrate catalysis differ. Chloride and bromide ion, but not fluoride, are about 100-fold more potent stimulators of binding than catalysis. When the active site Zn2+ ion is replaced by Co2+, catalysis was stimulated 2-fold, whereas binding activity was decreased by 70%.
Mol Pharmacol 1986 Feb
PMID:Characterization of angiotensin converting enzyme by [3H]captopril binding. 300 26

A series of polychlorinated hydroxybiphenyls (PCBs) has been tested for their binding activity to soluble uterine estrogen receptor protein. Competitive binding analysis was performed on 0-40% ammonium sulfate-enriched uterine cytosol receptor preparations which improved the binding activity for the PCB compounds by a factor of 10-40, by decreasing the nonspecific binding. The binding activities have been correlated to molecular properties supported by molecular modeling studies which emphasize the importance of conformational restriction. The estrogen receptor bound 4-hydroxy-2',4',6'-trichlorobiphenyl (4H2',4',6'TCB) with the greatest affinity, with the concentration of unlabeled inhibitor yielding half-maximal specific binding relative to estradiol (C50) being approximately 42 compared to estradiol, C50 approximately 1.0. PCB compounds that demonstrated appreciable receptor-binding activity were also active in vivo in stimulating uterine weight increases, whereas weak binders were inactive. The 4H2',4',6'TCB compound represents a high degree of conformational restriction around the interring bond due to the presence of two ortho-chlorine atoms. The other PCBs in this series, which show lower receptor-binding activity, vary in position of chlorine substituents and can assume multiple low energy conformations as a result of less hindrance to rotation around the interring bond.
Mol Pharmacol 1988 Jan
PMID:Estrogen receptor-binding activity of polychlorinated hydroxybiphenyls: conformationally restricted structural probes. 312 17

The influence of solvent viscosity on the kinetic parameters of the pyruvate reduction reaction catalyzed by lactate dehydrogenase has been investigated. The viscosity was adjusted by sucrose and glycerol solutions at concentrations from 0 to 44% and from 0 to 63%, respectively. The reaction rate decreased abruptly with an increase in viscosity. The study of different reaction stages (enzyme-substrate complex formation, catalysis, inhibitory complex decomposition, competitive inhibition by chlorine ions) revealed that the catalysis (and the related conformational changes) is the only stage (of the above mentioned) that depends markedly on the solvent viscosity. The reaction is insensitive to the changes in the dielectric properties of the solution induced by the addition of alcohols and dioxane. The observed power dependence of the rate constant on viscosity is explained in terms of Kramer's theory which considers the proton transition through the activation barrier to be a diffusion in the field of random forces. The influence of solvent viscosity on enzymic kinetics indicates a direct relation between solvent dynamics and relevant protein conformational movements.
Mol Biol (Mosk)
PMID:[Dynamic aspect of kinetics of reaction catalyzed by lactate dehydrogenase]. 318 25

One of the mutagenic byproducts associated with chlorinated humic waters and kraft pulp bleaching effluents was recently identified as 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone. This compound and several related chlorofuranones and precursors were synthesized and evaluated for direct-acting mutagenicity in Salmonella typhimurium tester strain TA100. Mutagenicity was greatest for 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone, its 5-methoxy derivative, and the precursor in their synthesis, 3-(dichloromethyl)-2,4,4-trichloro-2-butenoic acid. Several of the compounds were tested in the presence of added rat liver homogenate S9 fraction, and in all cases mutagenicity was substantially reduced. An important structural feature which may govern the mutagenic response in these instances appears to be the cis arrangement of CHCl2 and Cl substituents on a carbon-carbon double bond. These compounds may also be transformed in vitro to the same acyclic chlorine substituted alpha, beta-unsaturated aldehyde derivative, which is proposed to be the agent responsible for the observed mutagenicity.
Environ Mol Mutagen 1988
PMID:Mutagenic potency of chlorofuranones and related compounds in Salmonella. 327 97

The immunogenicity of a novel hapten, the anti-microbial agent, chlorhexidine (1,1'-hexamethylene bis [5-(p-chlorophenyl)biguanide]) was assessed in mice, using alum as adjuvant. The i.p. injection of electrostatically-linked chlorhexidine + keyhole limpet haemocyanin (KLH) mixtures induced low level primary IgG anti-chlorhexidine antibody synthesis. In contrast, covalently-linked chlorhexidine-KLH complexes induced both IgE and IgG anti-chlorhexidine antibody synthesis. Covalent binding was facilitated by the N-chlorination of secondary amide groups on the biguanide moeities of the chlorhexidine molecule. The immunogenicity of such complexes was related to the degree of conjugation of chlorhexidine to KLH; which, in turn, was related to the molarity of chlorine used to effect N-chlorination. Immune responses to covalently-linked complexes could be enhanced by carrier priming. The induction of low levels of IgG anti-hapten antibodies by electrostatically-linked complexes may reflect T cell-independent specific B cell activation, either by chlorhexidine itself or by a "pseudo-plurivalent" chlorhexidine + KLH antigen.
Mol Immunol 1987 Feb
PMID:Factors influencing the immunogenicity of the haptenic drug chlorhexidine in mice--Part I. Molecular requirements for the induction of IgE and IgG anti-hapten antibodies. 361 8

Fetal thymuses from C57BL/6 (B6) and DBA/2J (D2) mice from gestation day 14 or 15 were explanted and grown for 2 and 6 days in culture in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and a number of its congeners, known ligands of the Ah receptor (Ah, designating genetic locus for aryl hydrocarbon responsiveness). TCDD and 2,3,7,8-tetrachlorodibenzofuran (TCDBF) showed the same toxicity to B6 thymuses with a 50% inhibition of lymphoid development (EC50) at 10(-10) M concentration. 3,3',4,4'-Tetrachloroazoxybenzene (TCAOB) was only 2-10 times less effective, while the EC50 of 3,3',4,4'-tetrachlorobiphenyl (TCB) was around 10(-8) M (100 times higher than that of TCDD). TCBs with chlorine atoms in the position close to the biphenyl bridge were nontoxic even at 10(-5) M concentration. Thymuses exposed to TCDD, TCDBF, and TCAOB in vivo at teratogenic doses given to the mothers and explanted 24-48 hr later were smaller and inhibited in their early in vitro growth, but recovered slowly (less rapid for TCDD) as judged by lymphoid cell counts and [3H]thymidine incorporation. These results indicate a good correlation for this group of compounds between their activity as ligands of the Ah receptor and toxicity in vitro. Other ligands of the Ah receptor, namely 3-methylcholanthrene and beta-naphthoflavone, were inactive at the highest concentrations tested (10(-6) M). Thymuses from D2 mice, considered Ah receptor-defective, were nonsensitive to TCDD at the concentrations used (up to 3 X 10(-8) M) after 2 days in culture, indicating more than 100 times lower sensitivity as compared to B6 thymuses. After 6 days in culture, their sensitivity was however only 1 order of magnitude lower than that of B6 thymuses. Therefore "low sensitivity" of D2 thymuses may be at least partially overcome by prolonged exposure to TCDD in vitro.
Mol Pharmacol 1985 Jan
PMID:Fetal thymus organ culture as an in vitro model for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners. 396 25

The one-electron electrochemical reduction of diaziquone was analyzed using electron spin resonance and compared to its enzymatic reduction. Two analogues were used to help the analysis. The analogues contained chlorine atoms which substituted either the carboethoxyamino groups or the aziridine groups of the parent compound. The diaziquone free radical produced electrochemically in dimethyl sulfoxide exhibited an 11-line electron spin resonance spectrum. The hyperfine couplings responsible for this spectrum were due to the aziridine nitrogens (aNAz), and the imide hydrogens (aHNHR) and nitrogens (aNNHR) of the carboethoxyamino groups. The couplings had the following order of strength: (aNAz) greater than (aHNHR) greater than (aNNHR). The nuclei responsible for the (aNAz) and (aHNHR) coupling were found to be magnetically inequivalent. Adding water to the dimethyl sulfoxide solution of electrochemically reduced diaziquone changed its 11-line ESR spectrum to a 5-line spectrum identical to the one observed for enzymatically reduced diaziquone. Hence, the identity of this latter free radical was resolved. Electrochemically reduced free radicals of antitumor agents can be used to understand biologically reduced ones and thus explore drug activity-free radical structure relationships.
Mol Pharmacol 1984 Nov
PMID:Free radicals in quinone-containing antitumor agents. Electrochemical reduction of diaziquone (2,5-diaziridine-3,6-bis(carboethoxyamino)-1,4 -benzoquinone) and two analogues. 609 3

A high incidence of spontaneously formed urinary stone was found in the females of a jaundiced strain of rat developed from a cross between Gunn's rat and Wistar-Imamichi rat. In this colony, 42.3% of the females had urinary calculi. Elemental analyses of these urinary calculi were carried out with an analytical electron microscope, a high-resolution transmission electron microscope fitted with an energy dispersive type X-ray microanalyzer and a scanning device. In the surface and middle areas of the stone, the main components were recognized as magnesium (Mg) and phosphorus (P). In the central region of the stone, calcium (Ca) and phosphorus (P) were found as the main elements with trace amounts of sodium (Na), chlorine (Cl), and potassium (K). The analyses indicated that the spontaneous urinary stone consisted of phosphate salts with calcium or magnesium. In addition, the mass ratio of the Mg/P or Ca/P in the stones was calculated from X-ray pulse intensity ratios and compared with the mass ratio of a standard sample. The results suggested that the magnesium and phosphorus in the urinary stones existed as ammonium magnesium phosphate, MgNH4PO4, and the calcium and phosphorus as tribasic calcium phosphate, Ca3(PO4)2.
Exp Mol Pathol 1984 Feb
PMID:X-ray microanalysis of spontaneously formed urinary calculi in a jaundiced strain of rat. 669 2

The mechanism of metabolism of carbon tetrachloride (CCl4) to phosgene (COCl2) in rat liver microsomes was investigated. When the oxygen dependency of the reaction was studied, it was found that the rate of the reaction increased as the oxygen concentration in the reaction atmosphere was decreased from 100% to 5%. Decreasing the oxygen concentration below 5% caused a decrease in the rate of the reaction. The reaction was not inhibited by superoxide dismutase or catalase nor was it supported by cumene hydroperoxide. A reconstituted form of cytochrome P-450 from phenobarbital-pretreated rats metabolized CCl4 to COCl2. These results are consistent with a mechanism we call reductive oxygenation. The first step of the reaction is the cytochrome P-450-dependent reductive dechlorination of CCl4 to trichloromethyl radical (CCl3.). This intermediate is trapped by oxygen to form trichloromethylperoxyl radical (CCl3OO.), which decomposes to COCl2 and possibly an electrophilic form of chlorine.
Mol Pharmacol 1984 Mar
PMID:Reductive-oxygenation mechanism of metabolism of carbon tetrachloride to phosgene by cytochrome P-450. 670 May 77

The ideas of Harold Urey on the origin and evolution of the atmosphere have dominated thinking in this area for 3 decades. Recent progress in this area is reviewed, with particular emphasis on photochemical modeling studies of atmospheric evolution. Research into the paleoatmosphere can be divided into 3 distinct areas: (1) The photochemistry/chemistry of the prebiological paleoatmosphere, (2) the evolution of oxygen and the transition to an oxidizing atmosphere, and (3) the origin and evolution of ozone. Photochemical calculations indicate that the stability of a heavily reducing paleoatmosphere of CH4--NH3 was extremely shortlived, if such a prebiological atmosphere ever existed at all. A more mildly reducing early atmosphere of CO2--N2 is favored by photochemical considerations. Recent calculations of O2 in the prebiological paleoatmosphere vary from less than 10(-14) of present atmospheric level (PAL) to 10(-1) PAL. Clearly, additional work is indicated. The evolution of O3 as a function of O2 level has been investigated with increasingly detailed photochemical models that have included the photochemistry/chemistry of the oxygen, hydrogen, nitrogen, carbon, and chlorine species, as well as the effects of eddy transport, the rainout of water-soluble species, dry deposition and lightning as a source of trace atmospheric gases.
J Mol Evol 1982
PMID:The photochemistry of the paleoatmosphere. 709 75


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