Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.1 (alcohol dehydrogenase)
9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The quenching of liver alcohol dehydrogenase protein fluorescence at alkaline pH indicates two conformational states of the enzyme with a pKa of 9.8+/-0.2, shifted to 10.6+/-0.2 in D2O. NAD+ and 2-p-toluidinonaphthalene-6-sulfonate, a fluorescent probe competitive with coenzyme, bind to the acid conformation of the enzyme. The pKa of the protein-fluorescence quenching curve is shifted toward 7.6 in the presence of NAD+, and the ternary complex formation with NAD+ and trifluoroethanol results in a pH-independent maximal quench. At pH (pD) 10.5, the rate constant for NAD+ binding was 2.6 times faster in D2O2 than in H2O due to the shift of the pKa. Based on these results, a scheme has been proposed in which the state of protonation of an enzyme functional group with a pKa of 9.8 controls the conformational state of the enzyme. NAD+ binds to the acid conformation and subsequently causes another conformational change resulting in the perturbation of the pKa to 7.6. Alcohol then binds to the unprotonated form of the functional group with a pKa of 7.6 in the binary enzyme-NAD+ complex and converts the enzyme to the alkaline conformation. Thus, at neutral pH liver alcohol dehydrogenase undergoes two conformational changes en route to the ternary complex in which hydride transfer occurs.
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PMID:pH-dependent conformational states of horse liver alcohol dehydrogenase. 1 68

Horse liver alcohol dehydrogenase specifically carboxymethylated on cysteine-46 (a ligand to the zinc in the active site) or acetimidylated on 25 of the 30 lysine residues per subunit (including residue 228) was studied. The tryptophan fluorescence of these enzymes decreased by 35% as pH was increased, with an apparent pKa of 9.8 +/- 0.2, identical with that of native enzyme. Native enzyme in the presence of 30mM-imidazole, which displaces a water molecule ligated to the zinc, also had a pKa of 9.8. The ionoizable group is thus neither the water molecule nor one of the modified groups. Binding of NAD+ shifted the pKa for the fluorescence transition to 7.6 with native enzyme and to 9.0 with acetimidylated enzyme, but did not shift the pKa of carboxymethylated enzyme. Binding of NAD+ and trifluoroethanol, an unreactive alcohol, gave maximal fluorescence quenching at pH7 with all three enzymes. The acetimidylated enzyme--NAD+--trifluoroethanol complex had an apparent pKa of 5.0, but the pK of the native enzyme complex was experimentally inaccessible. The results are interpreted in terms of coupled equilibria between two different conformational states. On binding of NAD+, the modified enzymes apparently change conformation less readily than does native enzyme, but binding of alcohol can drive the change to completion.
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PMID:pH-dependent changes of intrinsic fluorescence of chemically modified liver alcohol dehydrogenases. 2 33

The binding of NAD+, NADH, and ADP-ribose to horse liver alcohol dehydrogenase has been studied calorimetrically as a function of pH at 25 degrees C. The enthalpy of NADH binding is 0 +/- 0.5 kcal mol-1 in the pH range 6 to 8.6. The enthalpy of NAD+ binding, however, varies with pH in a sigmoidal fashion and is -4.0 kcal mol(NAD)-1 at pH 6.0 and +4.5 kcal mol(NAD)-1 at pH 8.6 with an apparent pKa of 7.6 +/- 0.2. The enthalpy of proton ionization of the group on the enzyme is calculated to be in the range 8.8 to 9.8 kcal mol(H+)-1. In conjunction with the available thermodynamic data on the ionization of zinc-bound water in model compounds, it is concluded that the group with a pKa of 9.8 in the free enzyme and 7.6 in the enzyme . NAD+ binary complex is, most likely, the zinc-bound water molecule. Our studies with zinc-free enzyme provide further evidence for this conclusion. Therefore, the processes involving a conformational change of the enzyme upon NAD+ binding and the suggested mechanism of subsequent quenching of the fluorescence of Trp-314 implicating the participation of an ionized tyrosine group must be re-evaluated in the light of this thermodynamic study.
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PMID:The enthalpy of protolysis of liver alcohol dehydrogenase upon binding nicotinamide adenine dinucleotide. 3 45

Stimulation of urea and water transport by vasopressin (ADH) appears to occur via independent pathways. We examined the effects of altering serosal or mucosal bath pH on transport of water, urea, and sodium. Compared to bladders with a serosal bath pH of 7.4 to 8.0, reducing the serosal bath pH to 6.8 led to a 60% fall in ADH-stimulated osmotic water flow, without decreasing the permeability of urea. Raising the serosal pH to 9.5 had the opposite effect: urea permeability was inhibited by 40% without altering water flow. Exogenous cyclic AMP-stimulated water and urea permeabilities were not dissociated, but were changed in the same direction by alterations in serosal pH: serosal acidification enhanced the effect of exogenous cyclic AMP on both urea and water, whereas the cyclic AMP effect on both was diminished by serosal alkalinization. This was especially marked for urea, suggesting that an alteration in the urea response to cyclic AMP may be particularly important in defining vasopressin-stimulated urea permeability as the serosal bath pH is altered. Mucosal acidification increased short circuit current but decreased both the urea and water response to ADH and 8-bromo-cyclic AMP. The response to cyclic AMP was less consistent. Mucosal alkalinization did not cause significant changes in either basal or stimulated transport. The data demonstrate distinct and separable effects of bath pH alterations on each of the transport systems examined.
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PMID:pH-Dependence of water and solute transport in toad urinary bladder. 3 88

Cultures of methane- or methanol-utilizing microbes, including obligate (both types I and II) and facultative methylotrophic bacteria, obligate methanol utilizers, and methanol-grown yeasts were isolated from lake water of Warinanco Park, Linden, N.J., and lake and soil samples of Bayway Refinery, Linden, N.J. Resting-cell suspensions of these, and of other known C1-utilizing microbes, oxidized secondary alcohols to their corresponding methyl ketones. The product methyl ketones accumulated extracellularly. Succinate-grown cells of facultative methylotrophs did not oxidize secondary alcohols. Among the secondary alcohols, 2-butanol was oxidized at the highest rate. The optimal conditions for in vivo methyl ketone formation were compared among five different types of C1-utilizing microbes. Some enzymatic degradation of 2-butanone was observed. The product, 2-butanone, did not inhibit the oxidation of 2-butanol. The rate of the 2-butanone production was linear for the first 4 h of incubation for all five cultures tested. A yeast culture had the highest production rate. The optimum temperature for the production of 2-butanone was 35 degrees C for all the bacteria tested. The yeast culture had a higher temperature optimum (40 degrees C), and there was a reasonably high 2-butanone production rate even at 45 degrees C. Metal-chelating agents inhibit the production of 2-butanone, suggesting the involvement of metal(s) in the oxidation of secondary alcohols. Secondary alcohol dehydrogenase activity was found in the cell-free soluble extract of sonically disrupted cells. The cell-free system requires a cofactor, specifically nicotinamide adenine dinucleotide, for its activity. This is the first report of a nicotinamide adenine dinucleotide-dependent, secondary alcohol-specific enzyme.
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PMID:Microbial oxidation of gaseous hydrocarbons: production of methyl ketones from their corresponding secondary alcohols by methane- and methanol-grown microbes. 3 3

Mucosal acidification to pH 6.5 reduced by 88% the oxytocin- (2.2 x 10(-8) M) elicited increase of water permeability in frog urinary bladder. Mucosal alkalinization (pH 10.5) increased by as much as 200% the response to the same concentration of oxytocin. These effects were not observed when supramaximal concentrations of oxytocin were imployed. Similar changes were found when the serosal pH was modified. The hydrosmotic responses elicited by serosal hypertonicity or cyclic AMP plus theophylline were also affected by mucosal or serosal changes of the hydrogen in concentration, suggesting an effect at a post-cyclic AMP level. Important interactions were found between luminal pH and serosal hypertonicity when experimental conditions were employed similar to those observed in the collecting duct of mammalian nephron. Freeze-fracture studies showed that the number of intramembranous aggregates of particles induced by ADH in the luminal membrane was reduced by mucosal acidification and augmented by an increase in medium pH.
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PMID:Influence of mucosal and serosal pH on antidiuretic action in frog urinary bladder. 4 16

A double paraneoplasic syndrome with hypersecretion of ADH and ACTH revealed the presence of a small cell bronchial cancer in a man aged 62 years. Water and electrolyte anomalies due to the hypersecretions were of such a degree that an occlusive syndrome occurred. Very high levels of ADH and ACTH were found in the tumoral tissue. The measurement of these levels is rarely conducted at the present time but was able to define the mechanism of abnormal secretion of these two hormones in this case.
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PMID:[Double paraneoplastic syndrome and anaplastic carcinoma of the lung. ADH and ACTH levels in the tumoral tissue (author's transl)]. 4 61

The role of intercellular pathways in the ADH-dependent water transport was studied on the frog urinary bladder by means of acetylcholine (AC) and other cholinergic compounds. AC (10(-3) M) was found to cause a strong suppression of the pituitrin-stimulated water flow. Analogous effect was produced by AC on the osmotic flow stimulated by cyclic adenosine monophosphate (cAMP) and theolin. The antipituitrin effect was not reproduced either by nicotine, nor by potent M-cholinomimetic agents (methylfurmetide and F-2268), and was not prevented by M- and N-cholynolytic drugs (atropine, metacin, flaxedil, hexamethonium). However, the antipituitrin effect of AC was completely removed by the anticholinesterase drugs with different mode of action (eserine, proserine, armin, acridine iodmethylate, GD-42) in concentrations of 10(-6)--10(-3) M. It was concluded that the smooth muscles contraction with the subsequent closure of the intercellular spaces was not responsible for the antipituitrinic action of AC. This effect appears to be connected with cholinesterase activation. A possible role of the phosphoinositides in the water permeability regulation of the urinary bladder wall is discussed.
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PMID:[Effect of acetylcholine on the pituitrin induced osmotic flow of water through the wall of the frog urinary bladder]. 8 Oct 76

The effects of three tetracyclines, demethylchlortetracycline (DMC), minocycline (MNC), and oxytetracycline (OTC), on Na+ transport (measured as short-circuit current) were examined in toad urinary bladders mounted in modified Ussing chambers. During a 1-h incubation period serosal DMC (but not MNC or OTC) inhibited basal Na+ transport, whereas MNC (but not DMC or OTC) inhibited ADH-stimulated Na+ transport. MNC also inhibited cyclic AMP-stimulated Na+ transport. During longer incubation periods all three drugs inhibited basal Na+ transport. The DMC-induced inhibition of basal Na+ transport and the MNC-induced inhibition of ADH-stimulated Na+ transport were paralleled by an inhibition of the active conductance of the bladders. Thus, although all three drugs inhibit basal Na+ transport, only MNC inhibits ADH-stimulated Na+ transport. This effect does not correlate with the known effects of the tetracyclines on ADH-stimulated water flow or with drug-protein binding, and may be related to the greater lipid solubility of MNC.
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PMID:Tetracycline-induced inhibition of Na+ transport in the toad urinary bladder. 10 18

The hypothalamic-neurohypophyseal system functions to maintain plasma osmolality within narrow limits. It also is an important mechanism in maintaining normal body fluid volume. The system exerts its influence via release or inhibition of vasopressin (antidiuretic hormone, ADH) which acts on the kidney to decrease water excretion. Deficiency of ADH is usually due to hypothalamic-neurohypophyseal lesions (central diabetes insipidus) or insensitivity of the kidney to ADH (nephrogenic diabetes insipidus). These patients, if untreated, have the predictable result of dehydration, hyperosmolality, hypovolemia, and eventual death in severe cases. On the other hand, ADH excess of the syndrome of inappropriate ADH secretion due to a variety of causes promotes water retention, hypoosmolality and hyponatremia which, if untreated, may progress to convulsions, coma, and death. It is obviously important to diagnose accurately these pathologic states of hydration. Not only is initiation of treatment in general dependent upon recognition of the disease, but each type of pathologic hydration state has specific treatment which rewards both patient and physician with effective correction of the problem.
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PMID:Vasopressin: deficiency, excess and the syndrome of inappropriate antiduretic hormone secretion. 10 6


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