Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Chloride reduces the oxygen affinity of mammalian haemoglobin by acting as an allosteric effector that stabilizes the quaternary deoxy (T) structure. Perutz and others showed evidence that it does so by neutralizing electrostatic repulsion by an excess of positive charges in the cavity that runs through the centre of the molecule, but without binding to any specific site. On the basis of this proposal, any amino acid substitutions in the central cavity that halve the number of excess positive charges should halve the chloride effect, neutralization of the excess positive charges should inhibit it and introduction of additional positive charges should enhance it. Charge changes on the surface of the molecule should leave it unaltered. We have tested this proposal by measuring the chloride effects in several abnormal human haemoglobins with replacements of polar residues in the central cavity or on the surface that we happened to come across. They all proved consistent with the proposal. It appears that diffusible electrolytes can modify allosteric equilibria without necessarily binding to any specific site. Our proposal also implies that amino acid substitutions that make the central cavity more electropositive should destabilize the T-structure and therefore increase the oxygen affinity, while substitutions that make it more electronegative should do the reverse. A survey of all substitutions reported in the literature shows that this is true, with a few exceptions due to special stereochemical effects.
J Mol Biol 1994 Jun 17
PMID:The chloride effect in human haemoglobin. A new kind of allosteric mechanism. 800 67

In the framework of constructing a comprehensive transcript map of the human Xp22.3 region, we identified an evolutionary conserved CpG island and cloned the corresponding gene. The predicted 760 amino acid protein encoded by this gene contains 12 hydrophobic domains and shares significant sequence and structural similarities with all the previously isolated members of a recently identified family of voltage-gated chloride channels (the 'CIC family'). This gene, termed CICN4 (Chloride Channel 4), contains at least 10 exons spanning 60 to 80 kb on the X chromosome. In contrast to most genes isolated from the human Xp22.3 region, the CICN4 gene does not share homology with the Y chromosome and it is conserved in mouse and hamster. Expression studies revealed the presence of a 7.5 kb transcript which is particularly abundant in skeletal muscle and is also detectable in brain and heart. These data suggest that we have identified a new voltage-gated chloride channel which is encoded by a gene located in the distal short arm of the X chromosome.
Hum Mol Genet 1994 Apr
PMID:A gene from the Xp22.3 region shares homology with voltage-gated chloride channels. 806 96

Angiotensin converting enzyme (ACE) was measured in 15 sheep tissues by spectrophotometric assay with hippuryl-L-histidyl-L-leucine as substrate. Captopril inhibited the ACE activities of all the tissues. The ACE activity was highest in caput epididymidis, corpus epididymidis, cauda epididymidis, kidney and testis. The ACE activity was moderate in retina, little in cornea and lowest in lens. The greater increase in epididymal ACE activity than that of testicular ACE activity on maturation indicates that epididymal ACE may be highly sensitive to hormones. Chloride functioned as non-essential activator of corneal and retinal ACE. The ACE activities of sheep tissues are compared with those found in other species and probable role of ACE in different tissues is discussed.
Biochem Mol Biol Int 1993 Dec
PMID:Distribution and some properties of sheep (Ovis aries) angiotension converting enzyme. 813 3

Radioiodinated 11 beta-methoxy-(17 alpha,20E)iodovinylestradiol (11 beta-OMe-IVE2) shows high estrogen receptor (ER)-mediated uterus uptake and good potential as an ER-imaging agent. In order to examine the tolerance of the ER for modification about the iodovinyl substituent, we prepared the (17 alpha,20Z-chloro)21-chloro-21-iodovinylestradiol (4a) and several derivatives featuring 11 beta-methoxy (4b), 11 beta-ethoxy (4c) or 7 alpha-methyl (4d) substituents. All gem-dihalogen derivatives 4a-d were prepared from the 17 alpha-chloroethynyl precursors. The intermediate chlorostannylvinyl derivatives were obtained using tri-n-butyltin hydride and palladium acetate catalyst. Compounds 4a and 4b were labeled with 125I via their corresponding tin intermediates and their tissue distribution was studied in immature female rats. Addition of a 21-Cl to the 17 alpha-ethynylestradiols reduced ER binding affinity, except for the 11 beta-substituted analogs which showed a pronounced increase. Surprisingly, addition of a 21-Cl to the (17 alpha,20E)IVE2 resulted in increased ER binding affinities and augmented ER-mediated uterus uptake, which may result from the pronounced increase in the dipole moment of the molecule. Thus, further modifications at the C-21 position of IVE2 are well tolerated by the ER. However, addition of the 21-Cl also resulted in increased radioiodine uptake by the thyroid, much slower blood clearance and lower uterus to blood/nontarget ratios, suggesting increased in vivo instability of the C--I bond of the gem-chlorine-iodine atoms which may reflect the increase in steric and electronic interference.
J Steroid Biochem Mol Biol 1993 Nov
PMID:Synthesis, receptor binding and biodistribution of the gem-21-chloro-21-iodovinylestradiol derivatives. 824 Sep 84

Monochloramine has been suggested as an alternative disinfectant to chlorine to reduce levels of trihalomethanes in treated drinking water, but little is known of the toxicological properties and potential health implications of by-products specific to the chloramination process. Model aqueous fulvic acid solutions (200-400 mg C/liter), serving as surrogates for humic surface waters, were chloraminated over a range of molar Cl:C ratios from 1:40 to 1:2. The resulting by-products were extracted into diethyl ether at pH 2 and investigated with the Ames plate incorporation assay. Extractable mutagenicity increased with increasing chlorine and carbon dose up to about 30,000 revertants/liter at Cl:C ratios of 1:2. Mutagenicity was higher in Salmonella typhimurium strain TA100 than in strain TA98, and was decreased in the presence of S9, indicating that the mutagens formed were direct-acting and induced predominantly base-pair substitutions. Bovine serum albumin decreased slightly, and glutathione reduced greatly, the mutagenic activity detected in extracts. HPLC fractionation of the by-products indicated that most of the mutagenic activity was found in the earliest-eluting (most polar) fraction. The mutagenic by-products appeared to be qualitatively similar to 3-chloro-4-dichloromethyl-5-hydroxy-2-(5H)-furanone (MX) in their chromatographic behavior and responses to glutathione and bovine serum albumin, but were less readily detoxified by S9 than was MX.
Environ Mol Mutagen 1993
PMID:Formation and characterization of bacterial mutagens from reaction of the alternative disinfectant monochloramine with model aqueous solutions of fulvic acid. 846 27

The X-ray crystal structures of cytochrome P-450CAM complexed with both enantiomers of a chiral, multifunctional inhibitor have been refined to R-factors of 21.0% [(+)-enantiomer] and 19.6% [(-)-enantiomer] at approximately 2.1-A resolution. Binding of either enantiomer, both considerably larger than the natural substrate camphor, results in similar, dramatic structural changes in the enzyme. In contrast to all previous P-450CAM crystallographic structures, the Tyr96 side chain is not pointing "down" toward the heme but is rather directed "up" into the proposed substrate access channel. This conformational change is accompanied by the displacement of the Phe193 side chain out into the solvent at the enzyme surface. These changes are consistent with the assignment of this region of the enzyme as the access channel [Poulos et al. (1986) Biochemistry 25, 5314-5322] and suggest that several aromatic residues lining the channel may be involved in substrate recognition and channeling to the active site. The cation usually observed coordinated to the Tyr96 carbonyl oxygen is missing in the presence of the (+)-enantiomer but is present with the (-)-enantiomer. The Phe87 side chain, located near the inhibitor binding site, adopts different orientations depending upon which enantiomer is bound. Finally, electron density reveals that although the inhibitor enantiomers were dichlorinated as provided, when bound to P-450CAM the chlorine atoms are present at only 0-20% occupancy, probably reflecting selective binding of impurities in the samples. Coordinates of these inhibited P-450CAM complexes have been deposited in the Brookhaven Protein Data Bank [Bernstein et al. (1977) J. Mol. Biol. 112, 535-542].
 ...
PMID:Inhibitor-induced conformational change in cytochrome P-450CAM. 848 33

Rotaviruses have been linked to outbreaks of acute gastroenteritis of children in day-care centres and hospital paediatric wards. There is, therefore, the need for monitoring effective decontamination of such environments. We have evaluated the effects of seven different methods of disinfection/inactivation (four chemical and three physical) on rotavirus using the PCR and cell-culture methods. We observed that 6% H2O2, 2500 ppm chlorine, an ethano-phenolic disinfectant, u.v. irradiation and heat completely destroyed the infectivity of rotavirus as well as RNA amplifiable by PCR. On the other hand, treatment with 80% ethanol resulted in the loss of infectivity despite the fact that RNA was still amplifiable. Rotavirus subjected to drying over a 24 h period still retained amplifiable RNA but infectivity was reduced by 100-fold when compared to the control. This study demonstrated an agreement between PCR and cell-culture monitoring systems, however, PCR is a more rapid and sensitive assay.
Mol Cell Probes 1995 Oct
PMID:Evaluation of the effects of disinfectants on rotavirus RNA and infectivity by the polymerase chain reaction and cell-culture methods. 856 75

Drinking water samples were prepared in a pilot-scale treatment plant by chlorination (Cl2), chloramination (NH2Cl), ozonation (O3), or O3 followed by Cl2 or NH2Cl; and the nonvolatile acidic organics of the raw and treated waters were extracted by XAD/ethyl acetate and evaluated for mutagenicity in Salmonella (-S9). The extracts were 2-8 times more mutagenic in TA100 than in TA98, and the mutagenic potencies of the water extracts ranked similarly in both strains: Cl2 > O3 + Cl2 > NH2Cl > O3 + NH2Cl > O3 > raw. 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), which was estimated to account for approximately 20% of the mutagenic activity of the extracts, was shown to be the most potent compound tested thus far in a prophage-induction assay in Escherichia coli and a forward-mutation assay in Salmonella TM677. The mutations in approximately 2,000 revertants of TA98 and TA100 induced by MX and the water extracts were analyzed by colony probe hybridization and polymerase chain reaction/DNA sequence analysis. The water extracts and MX produced similar mutation spectra, which consisted in TA100 of predominantly of GC-->TA transversions in the second position of the CCC (or GGG) target of the hisG46 allele. This spectrum resembles that produced by large aromatic compounds and is distinct from that produced by alkylating agents and the semivolatile drinking water mutagen dichloroacetic acid. In TA98, MX and those water extracts resulting from the introduction of the chlorine atom produced 50-70% hotspot 2-base deletions and 30-50% complex frameshifts (frameshifts with an adjacent base substitution--mostly GC-->TA transversions as found in TA100). No other compound or mixture is known to induce such high frequencies of complex frameshifts. These results suggest that MX and "MX-like" compounds (possibly halogenated aromatics, such as halogenated polycyclic aromatic hydrocarbons) account for much of the mutagenic activity and specificity of the nonvolatile organics in drinking water and that these halogenated organics are especially capable of promoting misincorporation by the DNA replication complex. This study provides further evidence that the mutation spectrum of a complex mixture reflects the dominance of one or a few classes of chemical mutagens within the mixture.
Environ Mol Mutagen 1995
PMID:Mutation spectra in salmonella of chlorinated, chloraminated, or ozonated drinking water extracts: comparison to MX. 857 16

We investigated a novel molecular mechanism by which polychlorinated biphenyls (PCBs) alter microsomal Ca2+ transport with sarcoplasmic reticulum (SR) membranes isolated from skeletal and cardiac muscles. Aroclors with an intermediate weight percent of chlorine enhance by >6-fold the binding of 1 nM[3H]ryanodine to its conformationally sensitive site on the SR Ca2+ -release channel [i.e., ryanodine receptor (RyR)] with high potency (EC50=1.4 microM), whereas Aroclors with either high or low chlorine composition show little activity. Structure-activity studies with selected pentachlorobiphenyl congeners reveal a stringent structural requirement for chlorine substitution at the ortho-positions, with 2,2',3,5',6-pentachlorobiphenyl having the highest potency toward skeletal and cardiac isoforms of RyR (EC50=330 nM and 2 microM, respectively). In contrast, 3,3',4,4',5-pentachlorobiphenyl does not enhance ryanodine binding, suggesting that noncoplanarity of the biphenyl rings is required for channel activation. However, 2,2',4,6,6'-pentachlorobiphenyl is significantly less active toward RyR, suggesting that some degree of rotation about the biphenyl bond is required. 2,2',3,5',6-Pentachlorobiphenyl induces a dose-dependent release of Ca2+ from actively loaded SR vesicles with a maximum rate of 1.2 micromol mg-1 min-1 (EC50=1 microM), whereas 3,3',4,4',5-pentachlorobiphenyl (< / = microM) does not alter Ca2+ transport. The mechanism of PCB-induced channel activation involves a significant decrease in the inhibitory potency of Ca2+ and Mg2+ (20-fold and 100-fold, respectively). Neither 2,2',3,5',6- nor 3,3',4,4',5-pentachlorobiphenyl (< / = 10 microM) alters the activity of the skeletal isoform of sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase or the cardiac isoform of sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase, and PCB-induced Ca2+ release can be fully blocked by either microM ryanodine or ruthenium red. These results are the first to demonstrate a selective ryanodine receptor-mediated mechanism by which ortho-substituted PCBs alter microsomal Ca2+ transport and may have toxicological relevance.
Mol Pharmacol 1996 Apr
PMID:Ortho-substituted polychlorinated biphenyls alter calcium regulation by a ryanodine receptor-mediated mechanism: structural specificity toward skeletal- and cardiac-type microsomal calcium release channels. 860 4

Chlorination is a widely used method for disinfection of drinking water supplies. Reaction of chlorine with naturally present organic compounds can result in toxic by-products. One major disinfection by-product from the chlorination of drinking water is dichloroacetic acid (DCA). This chemical has been shown to be carcinogenic in rodents, yet little genotoxicity data are available to assess the possible role of DNA and/or chromosomal damage in this process. We have used the peripheral blood erythrocyte micronucleus (MN) assay and the alkaline single cell gel electrophoresis (SCG) technique to investigate the in vivo genotoxicity of DCA in bone marrow and blood leukocytes, respectively. The MN assay detects chromosome breakage and/or malsegregation, while the SCG assay detects DNA damage (e.g., single strand breaks, alkali-labile sites, crosslinking). Mice were exposed to this compound in drinking water, available ad libitum, for up to 31 weeks. Our results show a small but statistically significant dose-related increase in the frequency of micronucleated polychromatic erythrocytes (PCEs) after subchronic exposure to DCA for 9 days. In addition, at the highest dose of DCA tested (3.5 g/l), a small but significant increase in the frequency of micronucleated normochromatic erythrocytes (NCE) was detected following exposure for > or = 10 weeks. Coadministration of the antioxidant vitamin E did not affect the ability of DCA to induce this damage, indicating that the small induction of MN by DCA was probably not due to oxidative damage. Based on the lack of any difference observed in the proportion of kinetochore-positive micronuclei between the treated and control animals, we interpret MN as arising from clastogenic events. The SCG technique suggested the presence of DNA crosslinking in blood leukocytes in mice exposed to 3.5 g/l DCA for 28 days. These data provide evidence that DCA may be an extremely weak inducer of chromosome damage when provided to mice in drinking water under conditions which lead to increased levels of tumors.
Environ Mol Mutagen 1996
PMID:In vivo genotoxicity of dichloroacetic acid: evaluation with the mouse peripheral blood micronucleus assay and the single cell gel assay. 862 42


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