Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The presence of volume-activated chloride channels has been examined in neuroblastoma C1300 cells using the whole-cell configuration of the patch-clamp technique. Chloride channels could not be detected under isotonic conditions. However, hypotonic challenge induced slowly developed inward and outward anionic currents that exhibited outward rectification and inactivation at the most depolarizing potentials, features that were similar to the currents described in other cell preparations where volume-activated Cl- channels have been associated with the expression of P-glycoprotein. This hypotonicity-activated Cl- currents could be reversibly blocked by extracellular exposure to toremifene, a novel synthetic antioestrogen. The fact that toremifene and its analog tamoxifen, have been shown to block P-glycoprotein-associated chloride channels and to reverse P-glycoprotein associated multidrug resistance in a number of cell lines suggest that P-glycoprotein could be involved in the generation of hypotonic-induced chloride conductance in neuroblastoma cells.
Cell Mol Neurobiol 1996 Jun
PMID:Volume-activated chloride channels in neuroblastoma cells are blocked by the antiestrogen toremifene. 881 5

The roles of iron and other trace metals in the aetiology of heart and brain diseases has been a subject of keen research because of the ability of metal ions to participate in reactions involving free radicals, which have been implicated in many of these diseases. Unstained freeze dried tissue sections from the aorta of New Zealand white rabbits fed with a 1% cholesterol diet for 12 weeks were scanned with a 2 MeV proton beam using the National University of Singapore nuclear microscope facility. Results from 6 test and 4 control rabbits show that there is an average of seven-fold increase in iron and an average of nearly two-fold increase in phosphorus in the atherosclerotic lesion compared with healthy tissue. The increase in iron adds weight to the hypothesis that iron-catalyzed free radical reactions may be associated with the development of atherosclerosis. A depletion of other elements analyzed was seen in the lesion. Elemental mapping also showed the occurrence of granules rich in sodium, chlorine and potassium at the interface between lesioned and non-lesioned tissue.
Cell Mol Biol (Noisy-le-grand) 1996 Feb
PMID:Elemental changes in atherosclerotic lesions using nuclear microscopy. 883 71

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is an important target for chemotherapeutic agents used in the treatment of AIDS; the TIBO compounds are potent non-nucleoside inhibitors of HIV-1 RT (NNRTIs). Crystal structures of HIV-1 RT complexed with 8-Cl TIBO (R86183, IC50 = 4.6 nM) and 9-Cl TIBO (R82913, IC50 = 33 nM) have been determined at 3.0 A resolution. Mutant HIV-1 RT, containing Cys in place of Tyr at position 181 (Tyrl81Cys), is highly resistant to many NNRTIs and HIV-1 variants containing this mutation have been selected in both cell culture and clinical trials. We also report the crystal structure of Tyrl81Cys HIV-1 RT in complex with 8-Cl TIBO (IC50 = 130 nM) determined at 3.2 A resolution. Averaging of the electron density maps computed for different HIV-1 RT/NNRTI complexes and from diffraction datasets obtained using a synchrotron source from frozen (-165 degrees C) and cooled (-10 degrees C) crystals of the same complex was employed to improve the quality of electron density maps and to reduce model bias. The overall locations and conformations of the bound inhibitors in the complexes containing wild-type HIV-1 RT and the two TIBO inhibitors are very similar, as are the overall shapes and volumes of the non-nucleoside inhibitor-binding pocket (NNIBP). The major differences between the two wild-type HIV-1 RT/TIBO complexes occur in the vicinity of the TIBO chlorine substituents and involve the polypeptide segments around the beta5-beta6 connecting loop (residues 95 to 105) and the beta13-beta14 hairpin (residues 235 and 236). In all known structures of HIV-1 RT/NNRTI complexes, including these two, the position of the beta12-beta13 hairpin or the "primer grip" is significantly displaced relative to the position in the structure of HIV-1 RT complexed with a double-stranded DNA and in unliganded HIV-1 RT structures. Since the primer grip helps to position the template-primer, this displacement suggests that binding of NNRTIs would affect the relative positions of the primer terminus and the polymerase active site. This could explain biochemical data showing that NNRTI binding to HIV-1 RT reduces efficiency of the chemical step of DNA polymerization, but does not prevent binding of either dNTPs or DNA. When the structure of the Tyr181Cys mutant HIV-1 RT in complex with 8-Cl TIBO is compared with the corresponding structure containing wild-type HIV-1 RT, the overall conformations of Tyr181Cys and wild-type HIV-1 RT and of the 8-Cl TIBO inhibitors are very similar. Some positional changes in the polypeptide backbone of the beta6-beta10-beta9 sheet containing residue 181 are observed when the Tyr181Cys and wild-type complexes are compared, particularlty near residue Val179 of beta9. In the p51 subunit, the Cys181 side-chain is oriented in a similar direction to the Tyr181 side-chain in the wild-type complex. However, the electron density corresponding to the sulfur of the Cys181 side-chain in the p66 subunit is very weak, indicating that the thiol group is disordered, presumably because there is no significant interaction with either 8-Cl TIBO or nearby amino acid residues. In the mutant complex, there are slight rearrangements of the side-chains of other amino acid residues in the NNIBP and of the flexible dimethylallyl group of 8-Cl TIBO; these conformational changes could potentially compensate for the interactions that were lost when the relatively large tyrosine at position 181 was replaced by a less bulky cysteine residue. In the corresponding wild-type complex, Tyr181 iin the p66 subunit has significant interactions with the bound inhibitor and the position of the Tyr181 side-chain is well defined in both subunits. Apparently the Tyr181 --> Cys mutation eliminates favorable contacts of the aromatic ring of the tyrosine and the bou
J Mol Biol 1996 Dec 20
PMID:Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant. 900 Jun 32

The decreasing reactivity of tri-, di- and monochlorotriazine was utilized for the solid-phase construction of a combinatorial library with three randomized positions, using 20 amino acids and 50 amines as building blocks. The first chlorine atom was selectively substituted by coupling a large excess of trichlorotriazine to the support-bound amino acid, thus avoiding simultaneous substitution of the second chlorine. The second and third diversity positions were selectively introduced by coupling amines at different temperatures. Mixtures of model compounds were synthesized and analyzed, showing the correct representation of all expected components. A library composed of 12,000 compounds was generated using this method.
Mol Divers 1996 Oct
PMID:Library generation through successive substitution of trichlorotriazine. 923 36

The nu2 band of chlorine nitrate (ClONO2 ) near 1293 cm-1 has been measured in a molecular beam with a diode-laser spectrometer. The low rotational temperature of the molecular beam, approximately 23 K, simplifies the spectrum allowing essentially complete assignment of the 35 Cl and 37 Cl lines. An a /b hybrid band is observed with the a -type transition moment being approximately a factor of 2 larger than the b -type transition moment. An inverted shift of the band origins is found with the 37 Cl band origin blue shifted from the 35 Cl by +0.37 cm-1 . This isotopic shift is attributed to an unidentified anharmonic resonance. Precise spectroscopic constants for the bands of each isotopic species are determined to allow future simulations for modeling atmospheric transmission and for remote sensing applications.
J Mol Spectrosc 1997 Jun
PMID:Infrared Diode-Laser Molecular-Beam Spectrum of the nu2 Band of Chlorine Nitrate at 1293 cm-1 925 92

1. We studied the effects of selective chronic sodium depletion of chloride depletion on atrial natriuretic peptide receptor number in the subfornical organ and paraventricular nucleus of young rats. 2. Sodium or chloride depletion decreased plasma levels of atrial natriuretic peptide, increased plasma renin activity, and induced extracellular fluid volume contraction. Chloride depletion induced more significant changes in extracellular fluid volume contraction than sodium depletion. 3. In the subfornical organ, atrial natriuretic peptide receptor number significantly decreased (30%) after sodium depletion, while chloride depletion induced a smaller, not statistically significant decrease. Conversely, atrial natriuretic peptide receptors located in the paraventricular nucleus of young rats were not significantly affected by sodium or chloride depletion. 4. Water deprivation reversed the decrease in atrial natriuretic peptide receptors produced by sodium depletion. Water-deprived sodium-depleted rats actually had higher numbers of atrial natriuretic peptide receptors in the subfornical organ than control rats. These changes were associated with severe extracellular fluid volume contraction and up regulation of brain vasopressin mRNA steady-state levels. Thus, the direction of change in the number of subfornical organ atrial natriuretic peptide receptors was dependent on the degree of extracellular fluid volume contraction. 5. Our results suggest that atrial natriuretic peptide receptors located in the subfornical organ, and not in the paraventricular nucleus, are selectively regulated by sodium depletion and extracellular fluid volume contraction.
Cell Mol Neurobiol 1997 Oct
PMID:Selective chronic sodium or chloride depletion specifically modulates subfornical organ atrial natriuretic peptide receptor number in young rats. 935 88

High-resolution sub-Doppler Lamb-dip measurements were performed on the low-J pure rotational transitions of the hydrogen chloride isotopomers H35Cl, H37Cl, D35Cl, and D37Cl in the submillimeter-wave region up to 646 GHz. For the J = 1-0 transitions of the two HCl isotopomers, the hyperfine splitting due to the hydrogen nuclear spin-rotation interaction is resolved. Furthermore Doppler-limited lines of the DCl J = 3 <-- 2 transition around 965 GHz as well as hyperfine-resolved rotational transitions in the first excited vibrational state were recorded up to 1.22 THz. The new frequencies were analyzed in a global fit together with FIR data yielding a set of mass-invariant rotational parameters. Isotopically invariant hyperfine parameters were obtained also from the global fit. Inclusion of the precise results from molecular beam electric resonance measurements allowed the determination of higher orders of the vibrational and rotational expansion coefficients of the chlorine and hydrogen hyperfine interactions. The precise transition frequencies reported here should be useful as secondary calibration standards in the submillimeter-wave and terahertz region. Copyright 1998 Academic Press. Copyright 1998Academic Press
J Mol Spectrosc 1998 Jan
PMID:Precise Measurement of the Pure Rotational Submillimeter-Wave Spectrum of HCl and DCl in Their v = 0, 1 States 947 28

The catalytic mechanism for the enzyme, IMP cyclohydrolase, may involve a reaction intermediate with negative charge in the 2-position of the purine ring (Szabados, E., Hindmarsh, E., Phillips, L., Duggleby, R.G. & Christopherson, R.I. (1994) Biochemistry 33, 14237-14245). Three analogues of IMP have been synthesised where fluorine, chlorine or bromine has been substituted in the 2-position on the purine ring. These analogues with an electronegative substituent may resemble a reaction intermediate for IMP cyclohydrolase; 2-fluoro IMP is a potent inhibitor of the enzyme with a Ki value of 0.19 microM, while 2-chloro IMP has a Ki of 1.9 microM and 2-bromo IMP is not inhibitory. However, IMP cyclohydrolase is not inhibited in human CCRF-CEM leukaemia cells exposed to 2-fluoro inosine although it is toxic to these cells with an IC50 value of 4.9 microM.
Biochem Mol Biol Int 1998 Mar
PMID:Inosine-5'-monophosphate analogues as inhibitors of human IMP cyclohydrolase and cellular growth. 955 23

The target of these investigations was a study of covalent binding the antipsychotic drug clozapine and the tripeptide glutathione. Other workers, primarily using radioisotopes, have found many adducts of clozapine and glutathione. We wanted to see how well the chlorine atom in clozapine could serve as an alternate to the use of a radiolabel using the Chemical Reaction Interface/Mass Spectrometer technique with HPLC introduction (HPLC/CRIMS). Here, we examine the capabilities of two such schemes that were previously used with GC introduction: Cl detection with SO2 as the reactant gas; and Cl and S detection using NF3 as the reactant gas. Detecting chlorine as HCl with SO2 was accomplished giving linearity over an 80-fold range of sample size. Incubations of the drug and glutathione with a peroxidase/peroxide system system yielded several metabolites characterized as novel conjugates of clozapine by electrospray mass spectrometry. This tentative identification of two conjugates was confirmed by examining the incubation mixture with NF3 as the CRIMS reactant gas. The simultaneous appearance of both Cl and S is consistent with covalent binding of clozapine to glutathione. A nearly doubled ratio of S to Cl in one peak confirmed the presence of a di-glutathione conjugate. These experiments support our proposition that element selective detection of HPLC effluents with CRIMS can supply additional information, not previously available using radioisotopic methods.
Res Commun Mol Pathol Pharmacol 1998 Feb
PMID:Studying the reaction between clozapine and glutathione with element-selective detection. 958 88

The hyperfine structure in the J = 1 <-- 0 and J = 2 <-- 1 transitions of 35Cl3CCH3 and 35Cl237ClCCH3 was resolved by utilizing the sub-Doppler resolution of a pulsed supersonic beam, cavity Fourier transform microwave (FTMW) spectrometer. The complete inertial and principal quadrupole tensors of the chlorine nuclei are determined. The symmetric top treatment for 35Cl3CCH3 and the asymmetric top treatment for 35Cl237ClCCH3 are found to yield identical results for the principal tensor components of the 35Cl nucleus. The quadrupole asymmetry parameter eta for the chlorine nuclei in 1,1,1-trichloroethane is small, which indicates nearly cylindrical symmetry of the field gradient. Nevertheless, there is evidence for some deviation of the z symmetry axis of the field gradient from the direction of the C-Cl bond. Copyright 1998 Academic Press.
J Mol Spectrosc 1998 Jun
PMID:Nuclear Quadrupole Coupling in 1,1,1-Trichloroethane: Inertial and Principal Tensors for 35Cl and 37Cl. 964 17


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