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)

Formaldehyde dehydrogenase (PFDH) was isolated from the creatinine-decomposing bacterium Pseudomonas putida, and its gene has been cloned. PFDH is unique because it was the only enzyme that catalyzed the dehydrogenation of formaldehyde without glutathione. PFDH belongs to a zinc-containing alcohol dehydrogenase family. Quantitative analysis of the reaction products using NMR revealed that the enzyme is not simply a dehydrogenase but is an aldehyde dismutase catalyzing a simultaneous conversion of both aldehyde to carboxylate and aldehyde to alcohol. The enzyme contains a tightly bound cofactor of NAD+/NADH per subunit and is classified as a nicotinoprotein. The enzyme reaction can proceed without external addition of the nucleotide cofactor. The formaldehyde was crystallized using the hanging-drop vapor diffusion method with ammonium sulfate as a precipitant. The crystal structure was determined using the multiwavelength anomalous diffraction method with intrinsic zinc ions. The overall structure of PFDH is similar to that of a classic horse liver alcohol dehydrogenase. However, a comparison of these structures indicated that the insertion loop specifically found in PFDH may be responsible for the tight binding of the cofactor, thereby making PFDH a dismutase.
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PMID:[Structural and functional analysis of enzymes and their application to clinical analysis--study on Pseudomonas putida formaldehyde dehydrogenase]. 1240 Jan 61

Formaldehyde dehydrogenase from Pseudomonas putida (PFDH) is a member of the zinc-containing medium-chain alcohol dehydrogenase family. The pyridine nucleotide NAD(H) in PFDH, which is distinct from the coenzyme (as cosubstrate) in typical alcohol dehydrogenases (ADHs), is tightly but not covalently bound to the protein and acts as a cofactor. PFDH can catalyze aldehyde dismutations without an external addition of NAD(H). The structural basis of the tightly bound cofactor of PFDH is unknown. The crystal structure of PFDH has been solved by the multiwavelength anomalous diffraction method using intrinsic zinc ions and has been refined at a 1.65 A resolution. The 170-kDa homotetrameric PFDH molecule shows 222 point group symmetry. Although the secondary structure arrangement and the binding mode of catalytic and structural zinc ions in PFDH are similar to those of typical ADHs, a number of loop structures that differ between PFDH and ADHs in their lengths and conformations are observed. A comparison of the present structure of PFDH with that of horse liver ADH, a typical example of an ADH, reveals that a long insertion loop of PFDH shields the adenine part of the bound NAD(+) molecule from the solvent, and a tight hydrogen bond network exists between the insertion loop and the adenine part of the cofactor, which is unique to PFDH. This insertion loop is conserved completely among the aldehyde-dismutating formaldehyde dehydrogenases, whereas it is replaced by a short turn among typical ADHs. Thus, the insertion loop specifically found among the aldehyde-dismutating formaldehyde dehydrogenases is responsible for the tight cofactor binding of these enzymes and explains why PFDH can effectively catalyze alternate oxidation and reduction of aldehydes without the release of cofactor molecule from the enzyme.
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PMID:Crystal structure of formaldehyde dehydrogenase from Pseudomonas putida: the structural origin of the tightly bound cofactor in nicotinoprotein dehydrogenases. 1244 86

Human Class III alcohol dehydrogenase (ADH), also known as glutathione-dependent formaldehyde dehydrogenase plays an important role in the formaldehyde detoxification and reduction of the nitric oxide metabolite s-nitrosoglutathione (GSNO). It follows a random bi bi kinetic mechanism and prefers bulkier substrates like long chain primary alcohols and glutathione adducts like s-hydroxymethylglutathione and GSNO over smaller alcohols like ethanol. The structure of the FDH.NAD(H) binary complex reported here, in conjunction with the other complexes of FDH, provide the structural basis of the kinetic observations. These structures show that the apoenzyme has a semi-open domain conformation that permits random random addition of alcohol or NAD(H). Moreover, there is no significant domain movement upon binding of the coenzyme or the substrate, 12-hydroxydodecanoic acid. Interestingly, two active site zinc coordination environments are observed in FDH. In the apoenzyme, the active site zinc is coordinated to Cys44, His66, Cys173 and a water molecule. In the FDH.NAD(H) binary complex reported here, Glu67 is added to the coordination environment of the active site zinc and the distance between the water molecule and zinc is increased. This change in the zinc coordination, brought about by the displacement of zinc of about 2 A towards Glu67 could promote substrate exchange at the active site metal during catalysis.
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PMID:Structure-function relationships in human Class III alcohol dehydrogenase (formaldehyde dehydrogenase). 1260 4

Gene and genome duplications in the vertebrate lineage explain the complexity of extant gene families. Among these, the medium-chain alcohol dehydrogenase (ADH), which expanded by tandem duplications after the cephalochordate-vertebrate split, is a good model with which to analyze the evolution of gene function. Although the ancestral member of this family, ADH3, has been strictly conserved throughout animal evolution, its physiological role is still controversial. Previous evidence indicates that it contributes to formaldehyde cytoprotection, retinoic acid metabolism, and nitric oxide homeostasis. We performed in situ hybridization during Drosophila, ascidian (Ciona intestinalis), and zebrafish (Danio rerio) development. We showed that Adh3 expression was restricted to the fat body in Drosophila embryos at stage 17 and to the anterior endoderm in C. intestinalis tail bud, whereas in the zebrafish 2.5-day larvae the signal appeared widespread. A more comprehensive expression analysis including amphioxus and mice revealed that ancestral Adh3 was tissue specific, whereas a widespread expression was later attained in vertebrates. These variations occurred concomitantly with the expansion of the ADH family and the acquisition of new functions but were unlinked to the genomic changes that led to the transition from fractional to global methylation in vertebrates. Our data challenge the housekeeping role of ADH3 and question its involvement in the prevertebrate retinoic acid pathway.
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PMID:Comparative expression analysis of Adh3 during arthropod, urochordate, cephalochordate, and vertebrate development challenges its predicted housekeeping role. 1262 32

Mouse embryos are more sensitive than rat embryos in response to methanol (CH(3)OH) and its ability to elicit developmental abnormalities. Intrinsic differences in the metabolism of CH(3)OH to formaldehyde (HCHO) and formic acid (HCOOH) by the enzymes alcohol dehydrogenase (ADH1), formaldehyde dehydrogenase (ADH3), and catalase may contribute to the observed species sensitivity. Specific activities for enzymes involved in CH(3)OH metabolism were determined in rat and mouse conceptuses during the organogenesis period of 8-25 somites. Spatial activity relationships were also compared separately in heads, hearts, trunks, and the visceral yolk sac (VYS) from early (7-12 somites) and late (20-22 somites) organogenesis-stage rat and mouse embryos. Catalase activities were similar between rat and mouse conceptuses. In the mouse heart, catalase activities were consistently lower when compared to other tissues. Specific activities for catalase were consistently highest in the VYS of both species when compared to other tissues of the embryo. These activities were highly significant in the 6-12 somite VYS. ADH1 activities were significantly higher in embryos when compared to VYS in both species, except for a 27% lower activity in the early 8-10 somite mouse embryo. Mouse ADH1 activities in the VYS were significantly lower throughout the organogenesis period when compared to the rat VYS or embryos of either species. Mouse activities were lower overall in specific tissues of the embryo but maintained the same relative proportions as in the rat. ADH3 activities in the rat VYS were significantly higher by 20% than those in the mouse. Mouse embryo ADH3 activities were slow to mature, starting at a level 42% below rat, and failed to reach optimal levels until the 14-16-somite stage. Heart ADH3 activities were also significantly lower in the mouse embryo at the 7-12-somite stage. Both species have lower ADH3 activities in the early heart, relative to other embryonic tissues. These results show a more slowly maturing capacity of the mouse embryo to remove HCHO, which provides a rationale for increased sensitivity of this species to CH(3)OH-induced embryotoxicity and teratogenicity.
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PMID:Methanol metabolism and embryotoxicity in rat and mouse conceptuses: comparisons of alcohol dehydrogenase (ADH1), formaldehyde dehydrogenase (ADH3), and catalase. 1275 5

Mushroom alcohol dehydrogenase (ADH) from Agaricus bisporus (common mushroom, champignon) was purified to apparent homogeneity. One set of ADH isozymes was found, with specificity against formaldehyde/glutathione. It had two highly similar subunits arranged in a three-member isozyme set of dimers with indistinguishable activity. Determination of the primary structure by a combination of chemical, mass spectrometric and cDNA sequence analyses, correlated with molecular modeling towards human ADHs, showed that the active site residues are of class III ADH type, and that the subunit differences affect other residues. Class I and III forms of ADHs characterized define conserved substrate-binding residues (three and eight, respectively) useful for recognition of these enzymes in any organism.
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PMID:Class III alcohol dehydrogenase: consistent pattern complemented with the mushroom enzyme. 1496 Mar 2

Methyl formate synthesis during growth on methanol by methylotrophic yeasts has been considered to play a role in formaldehyde detoxification. An enzyme that catalyses methyl formate synthesis was purified from methylotrophic yeasts, and was suggested to belong to a family of alcohol dehydrogenases (ADHs). In this study we report the gene cloning and gene disruption analysis of three ADH-encoding genes in the methylotrophic yeast Candida boidinii (CbADH1, CbADH2 and CbADH3) in order to clarify the physiological role of methyl formate synthesis. From the primary structures of these three genes, CbAdh1 was shown to be cytosolic and CbAdh2 and CbAdh3 were mitochondrial enzymes. Gene products of CbADH1, CbADH2 and CbADH3 expressed in Escherichia coli showed both ADH- and methyl formate-synthesizing activities. The results of gene-disruption analyses suggested that methyl formate synthesis was mainly catalysed by a cytosolic ADH (CbAdh1), and this enzyme contributed to formaldehyde detoxification through glutathione-independent formaldehyde oxidation during growth on methanol by methylotrophic yeasts.
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PMID:Alcohol dehydrogenases that catalyse methyl formate synthesis participate in formaldehyde detoxification in the methylotrophic yeast Candida boidinii. 1504 94

In the first pass methanol biotransformation three enzymatic systems: alcohol dehydrogenase (ADH), microsomal alcohol oxidising system (MEOS) linked with cytochrome P-450 and catalase are involved. Because of the toxicity of methanol, which is directly caused by its toxic metabolites, the major task in clinical toxicology is to inhibit each of these enzymes to protect human life. The aim of this investigation was to check the influence of some effective inhibitors of ADH and MEOS: 4-methylpyrazole, cimetidine, EDTA and 1,10-phenantroline on the activity of catalase with methanol as a substrate and the comparison with 3-amino-1,2,4-triasole. Catalase activity in rat hepatic homogenates was measured spectrophotometrically in vitro at physiological pH 7.4 and temp. 37 degrees C, assaying the degree of methanol oxidation according to Handler and Thurman. The quantity of arising formaldehyde was measured according with the method of Nash. Our results have shown that catalase activity was inhibited to different extents by all investigated compounds at concentrations of 10(-3) mol/l, 2 x 10(-4) mol/l, 10(-4) mol/l, 2 x 10(-5) mol/l, 10(-5) mol/l. 1,10-Phenantroline was found to be a highly effective inhibitor in comparison with aminotriasole. 4-Methylpyrazole, EDTA, 1,10-phenantroline and aminotriasole are catalase competitive inhibitors and cimetidine is non-competitive inhibitor. 4-Methylpyrazole has shown higher affinity to the enzyme than aminotriasole.
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PMID:[Activity of catalase after administration of some ADH and MEOS inhibitors: in vitro investigation in rat liver homogenates]. 1505 35

A one-pot synthesis of isotopically labeled R-[6-xH]N5,N10-methylene-5,6,7,8-tetrahydrofolate (CH2H4F) is presented, where x=1, 2, or 3 represents hydrogen, deuterium, or tritium, respectively. The current procedure offers high-yield, high-purity, and microscale-quantity synthesis. In this procedure, two enzymes were used simultaneously in the reaction mixture. The first was Thermoanaerobium brockii alcohol dehydrogenase, which stereospecifically catalyzed a hydride transfer from C-2-labeled isopropanol to the re face of oxidized nicotinamide adenine dinucleotide phosphate to form R-[4-xH]-labeled reduced nicotinamide adenine dinucleotide phosphate. The second enzyme, Escherichia coli dihydrofolate reductase, used the xH to reduce 7,8-dihydrofolate (H2F) to form S-[6-xH]5,6,7,8-tetrahydrofolate (S-[6-xH]H4F). The enzymatic reactions were followed by chemical trapping of S-[6-xH]H4F with formaldehyde to form the final product. Product purification was carried out in a single step by reverse phase high-pressure liquid chromatography separation followed by lyophilization. Two analytical methods were developed to follow the reaction progress. Finally, the utility of the labeled cofactor in mechanistic studies of thymidylate synthase is demonstrated by measuring the tritium kinetic isotope effect on the enzyme's second order rate constant.
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PMID:Microscale synthesis of isotopically labeled R-[6-xH]N5,N10-methylene-5,6,7,8-tetrahydrofolate as a cofactor for thymidylate synthase. 1508 6

There persists a need for potent and safe inhibitors of alcohol dehydrogenase (ADH), to effectively treat methanol poisoning by slowing its rate of biotransformation to there toxic products, formaldehyde and formic acid. Only a few former papers have reported on the significant effectiveness of L-carnitine in treating ethanol poisoning as well as alcohol abuse. As are no reports on the effectiveness of L-carnitine in treating methanol poisoning till now, the current studies were conducted to investigate the influence of L-carnitine on both oxydative metabolism and elimination of methanol in rats. Male Sprague-Dawley rats, aged 3 months with the body weight of 200-230 g were divided into 6 groups at random, with two of the groups considered to be control. Rats were given drinking water (control) or methanol in two different doses of 3220 mg/kg b.m. or 6440 mg/kg b.m. intragastrically and 0.9% NaCl (control) or 6.2 mmol/kg b.m. of L-carnitine intraperitionelly. Within 96 hours after the administration of methanol and 0.9% NaCl or L-carnitine, the urine was collected and then the animals were decapitated. To determine methanol there were taken blood samples for clot, and to determine carnitine and its derivatives blood was taken into heparinized test tubes. During the autopsy liver was also secured. In all the experimental time points stated the methanol concentrations in blood, urine and liver homogenate were determined by a head-space gas chromatography.
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PMID:The influence of L-carnitine on methanol biotransformation in rats. 1508 38


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