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 crystal structure of the human class III chi chi alcohol dehydrogenase (ADH) in a binary complex with NAD+(gamma) was solved to 2.7 A resolution by molecular replacement with human class I beta1 beta1 ADH. chi chi ADH catalyzes the oxidation of long-chain alcohols such as omega-hydroxy fatty acids as well as S-hydroxymethyl-glutathione, a spontaneous adduct between formaldehyde and glutathione. There are two subunits per asymmetric unit in the chi chi ADH structure. Both subunits display a semi-open conformation of the catalytic domain. This conformation is half-way between the open and closed conformations described for the horse EE ADH enzyme. The semi-open conformation and key changes in elements of secondary structure provide a structural basis for the ability of chi chi ADH to bind S-hydroxymethyl-glutathione and 10-hydroxydecanoate. Direct coordination of the catalytic zinc ion by Glu68 creates a novel environment for the catalytic zinc ion in chi chi ADH. This new configuration of the catalytic zinc is similar to an intermediate for horse EE ADH proposed through theoretical computations and is consistent with the spectroscopic data of the Co(II)-substituted chi chi enzyme. The position for residue His47 in the chi chi ADH structure suggests His47 may function both as a catalytic base for proton transfer and in the binding of the adenosine phosphate of NAD(H). Modeling of substrate binding to this enzyme structure is consistent with prior mutagenesis data which showed that both Asp57 and Arg115 contribute to glutathione binding and that Arg115 contributes to the binding of omega-hydroxy fatty acids and identifies additional residues which may contribute to substrate binding.
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PMID:Structure of human chi chi alcohol dehydrogenase: a glutathione-dependent formaldehyde dehydrogenase. 901 47

Methyl formate synthase, which catalyzes methyl formate formation during the growth of methylotrophic yeasts, was purified to homogeneity from methanol-grown Candida boidinii and Pichia methanolica cells. Both purified enzymes were tetrameric, with identical subunits with molecular masses of 42 to 45 kDa, containing two atoms of zinc per subunit. The enzymes catalyze NAD(+)-linked dehydrogenation of the hydroxyl group of the hemiacetal adduct [CH2(OH)OCH3] of methanol and formaldehyde, leading to the formation of a stoichiometric amount of methyl formate. Although neither methanol nor formaldehyde alone acted as a substrate for the enzymes, they showed simple NAD(+)-linked alcohol dehydrogenase activity toward aliphatic long-chain alcohols such as octanol, showing that they belong to the class III alcohol dehydrogenase family. The methyl formate synthase activity of C. boidinii was found in the mitochondrial fraction in subcellular fractionation experiments, suggesting that methyl formate synthase is a homolog of Saccharomyces cerevisiae Adh3p. These results indicate that formaldehyde could be oxidized in a glutathione-independent manner by methyl formate synthase in methylotrophic yeasts. The significance of methyl formate synthase in both formaldehyde resistance and energy metabolism is also discussed.
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PMID:Purification and properties of methyl formate synthase, a mitochondrial alcohol dehydrogenase, participating in formaldehyde oxidation in methylotrophic yeasts. 914 7

A water-soluble ester, methyl formate, was detected as a metabolite in the culture medium of methylotrophic yeasts. Methyl formate synthase, which catalyses NAD(+)-dependent dehydrogenation of the hemiacetal adduct of methanol and formaldehyde, catalyses the ester synthesis. The enzyme activity was induced on a methanol medium and was increased further by the addition of formaldehyde. In the reaction system using intact cells of Pichia methanolica AKU 4262, 135 mM (8.1 g/liter) methyl formate was produced from 2 M methanol. This is a new biological process for ester synthesis that couples spontaneous formation of hemiacetal and alcohol dehydrogenase.
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PMID:Ester synthesis by NAD(+)-dependent dehydrogenation of hemiacetal: production of methyl formate by cells of methylotrophic yeasts. 930 Nov 24

Cell-free extracts of Methanosarcina barkeri DSM 804 showed alcohol dehydrogenase activity under aerobic conditions when N,N-dimethyl-4-nitrosoaniline (NDMA) was used as an artificial electron acceptor. The NDMA-dependent alcohol dehydrogenase (NDMA-ADH) was purified to approximate homogeneity by column chromatography. It is most probably a homodimeric enzyme consisting of subunits of 45 kDa, the native molecular mass estimated by gel filtration being about 87 kDa. The purified protein had an isoelectric point of 4.3. It possesses a tightly but noncovalently bound NADP(H) cofactor. Each subunit contains 1 mol NADP(H)/mol, about 2 mol Zn2+/mol and significant amounts of magnesium. The purified enzyme preferably oxidized primary alcohols (including benzyl alcohol). NDMA-ADH from M. barkeri also catalyzed the stoichiometric dismutation of aldehydes, especially higher aliphatic aldehydes, to form equimolar amounts of the corresponding alcohol and acid without addition of an electron carrier. The enzyme did not catalyze the dehydrogenation of methanol or the disproportionation of formaldehyde and therefore is not directly involved in methanogenesis. An alignment of the N-terminal amino acid sequence of the enzyme with the sequences of other alcohol dehydrogenases from methanogenic and nonmethanogenic bacteria indicated no significant identity. Nevertheless there was a quite interesting sequence similarity in the first 30 N-terminal amino acids to plant cinnamyl alcohol dehydrogenase. NDMA-ADH from M. barkeri is a novel type of alcohol dehydrogenase in methanogenic bacteria.
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PMID:Purification and characterization of an alcohol:N,N-dimethyl-4-nitrosoaniline oxidoreductase from the methanogen Methanosarcina barkeri DSM 804 strain Fusaro. 934 43

An organism tentatively identified as Ralstonia eutropha was isolated from enrichment cultures containing tetrahydrofurfuryl alcohol (THFA) as the sole source of carbon and energy. The strain was able to tolerate up to 200 mM THFA in mineral salt medium. The degradation was initiated by an inducible ferricyanide-dependent alcohol dehydrogenase (ADH) which was detected in the soluble fraction of cell extracts. The enzyme catalyzed the oxidation of THFA to the corresponding tetrahydrofuran-2-carboxylic acid. Studies with n-pentanol as the substrate revealed that the corresponding aldehyde was released as a free intermediate. The enzyme was purified 211-fold to apparent homogeneity and could be identified as a quinohemoprotein containing one pyrroloquinoline quinone and one covalently bound heme c per monomer. It was a monomer of 73 kDa and had an isoelectric point of 9.1. A broad substrate spectrum was obtained for the enzyme, which converted different primary alcohols, starting from C2 compounds, secondary alcohols, diols, polyethylene glycol 6000, and aldehydes, including formaldehyde. A sequence identity of 65% with a quinohemoprotein ADH from Comamonas testosteroni was found by comparing 36 N-terminal amino acids. The ferricyanide-dependent ADH activity was induced during growth on different alcohols except ethanol. In addition to this activity, an NAD-dependent ADH was present depending on the alcohol used as the carbon source.
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PMID:Degradation of tetrahydrofurfuryl alcohol by Ralstonia eutropha is initiated by an inducible pyrroloquinoline quinone-dependent alcohol dehydrogenase. 940 10

The so far unelucidated pathway of formation of ethanol, one of the major end products of the fermentative metabolism of the amitochondriate protist, Giardia lamblia, was examined. Two NAD-dependent enzymatic activities, an acetaldehyde dehydrogenase (CoA-acetylating) (EC 1.2.1.10) and an alcohol dehydrogenase (EC 1.1.1.1) were detected. These are assumed to catalyze the formation of ethanol from acetyl-CoA via acetaldehyde. The first activity, present on a 95-kDa protein, was purified. It catalyzed the reversible interconversion of acetyl-CoA to acetaldehyde and CoA-SH with NAD but not NADP as cofactor. In the direction of aldehyde formation acetyl-CoA was the preferred substrate. Propionyl-CoA and isobutyryl-CoA were reduced with lower efficiency while succinyl-CoA and benzoyl-CoA were not. In the direction of acyl-CoA formation, acetaldehyde was the preferred substrate. Propionaldehyde and isobutyraldehyde were utilized at a lower efficiency while formaldehyde, benzaldehyde, and acetone were not. The second activity, a primary alcohol dehydrogenase, was also NAD-specific and used preferentially ethanol as substrate. Sequencing data of peptides from the purified protein and Northern and Southern analysis indicated that the same polypeptide, which belongs to the bifunctional aldehyde/alcohol dehydrogenase enzyme family, carried both activities. These activities define the pathway to ethanol in G. lamblia as a two step-processes: (i) acetyl-CoA + NADH<-->acetaldehyde + CoA-SH + NAD+ and (ii) acetaldehyde + NADH<-->ethanol + NAD+. In contrast to most eukaryotes in which ethanol formation proceeds from pyruvate via acetaldehyde, the G. lamblia pathway departs from acetyl-CoA, a more distal product of extended glycolysis.
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PMID:Aldehyde dehydrogenase (CoA-acetylating) and the mechanism of ethanol formation in the amitochondriate protist, Giardia lamblia. 963 98

Some methylotrophic yeasts produce methyl formate from methanol and formaldehyde via hemiacetal formation. We investigated Saccharomyces cerevisiae to find whether this yeast has a carboxylate ester producing pathway that proceeds via hemiacetal dehydrogenation. We confirmed that the purified alcohol dehydrogenase (Adh) protein from S. cerevisiae can catalyze the production of esters. High specific activities were observed toward the hemiacetals corresponding to the primary alcohols when ether groups were substituted for methylene groups, resulting in the formation of formate esters. Both ADH and methyl formate synthesizing activities were sharply reduced in the delta adh1 delta adh2 mutant. The ADH1 and ADH2 genes encode the major Adh proteins in S. cerevisiae. Thus, it was concluded that the S. cerevisiae Adh protein catalyzes activities for the production of certain carboxylate esters.
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PMID:Hemiacetal dehydrogenation activity of alcohol dehydrogenases in Saccharomyces cerevisiae. 983 32

Targeting of mouse alcohol dehydrogenase genes Adh1, Adh3, and Adh4 resulted in null mutant mice that all developed and reproduced apparently normally but differed markedly in clearance of ethanol and formaldehyde plus metabolism of retinol to the signaling molecule retinoic acid. Following administration of an intoxicating dose of ethanol, Adh1 -/- mice, and to a lesser extent Adh4 -/- mice, but not Adh3 -/- mice, displayed significant reductions in blood ethanol clearance. Ethanol-induced sleep was significantly longer only in Adh1 -/- mice. The incidence of embryonic resorption following ethanol administration was increased 3-fold in Adh1 -/- mice and 1.5-fold in Adh4 -/- mice but was unchanged in Adh3 -/- mice. Formaldehyde toxicity studies revealed that only Adh3 -/- mice had a significantly reduced LD50 value. Retinoic acid production following retinol administration was reduced 4.8-fold in Adh1 -/- mice and 8.5-fold in Adh4 -/- mice. Thus, Adh1 and Adh4 demonstrate overlapping functions in ethanol and retinol metabolism in vivo, whereas Adh3 plays no role with these substrates but instead functions in formaldehyde metabolism. Redundant roles for Adh1 and Adh4 in retinoic acid production may explain the apparent normal development of mutant mice.
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PMID:Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid. 1035 22

Airway epithelial surface is the primary target of airborne pollutants. To estimate the distribution of xenobiotic-metabolizing enzymes in the respiratory tract of dogs, epithelia from different airway sites of four animals were analyzed for metabolism of sulfite (sulfite oxidase) and formaldehyde (formaldehyde dehydrogenase and aldehyde dehydrogenase). In addition, glutathione S-transferases were assayed using several model substrates. Enzyme activities were compared with those found in liver parenchyma. The activity of sulfite oxidase was found to be comparable in nose, trachea, and proximal and medium bronchi, but appeared to be lower in lung parenchyma of most animals. In contrast, hepatic sulfite oxidase activity of these animals was substantially higher compared to that in airway epithelia. The activity of glutathione-dependent formaldehyde dehydrogenase (FDH) appeared to be highest in nose and lowest in distal bronchi, lung, and liver parenchyma. The distribution pattern of the glutathione-independent aldehyde dehydrogenase (AldDH) in the respiratory tract was different from that of FDH. Levels of AldDH were about 5- to 10-fold lower than those of FDH, suggesting that AldDH is of minor importance for pulmonary formaldehyde detoxification. With regard to ethanol detoxification by a class I alcohol dehydrogenase (ADH), no measurable enzyme activity could be detected at most respiratory sites contrary to the high activity found in liver parenchyma. Regarding glutathione S-transferases (GSTs), different distributions of enzyme activities were found in the large and small airways when using three substrates. The 1-chloro-2,4-dinitrobenzene (CDNB)-related activities in the cytosolic fraction of the upper (nose, trachea) and lower airways (proximal, medium and distal bronchi) were higher than those in the microsomal fraction. Interestingly, there was no difference between CDNB-related activities in the cytosolic and microsomal fraction of the liver. Highest cytosolic activities were found in the nose, and were comparable to those detected in the liver parenchyma. The cytosolic 1,2-dichloro-4-nitrobenzene (DCNB)-related activities in the nose, proximal bronchi, and lung parenchyma were appeared to be markedly higher than those in trachea and medium and distal bronchi, while the microsomal activities were not detectable at most respiratory sites. In contrast, distinctly higher activities were measured in both fractions of liver tissue. Cytosolic 1, 2-epoxy-3-(p-nitrophenoxy)-propane (EPNP)-related activities were present in upper and lower airways including lung parenchyma at comparable levels, while in liver tissue the mean activities were distinctly lower. No EPNP-related activities were found in the microsomal fractions. In conclusion, most xenobiotic-metabolizing enzymes investigated in this study could be detected in epithelia of various respiratory sites. The most outstanding result revealed higher levels of FDH activity in the nose and downstream to the medium bronchi in comparison to those found in the small airways, lung, and liver tissue. Similarly, the EPNP-related GST exhibited a distinctly higher activity at all respiratory sites compared to the activity in liver tissue, suggesting a different regulation of this enzyme in lung and liver.
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PMID:Xenobiotic-metabolizing enzymes in the canine respiratory tract. 1038 Jan 57

The distributions of class III alcohol dehydrogenase (ADH), a glutathione-dependent formaldehyde dehydrogenase, and class I ADH in the human brain were examined immunohistochemically. The most intense immunostaining of class III ADH was observed in the dendrites and cytoplasm of cerebellar Purkinje cells. Scattered cerebral cortical neurons in layers IV and V, and some hippocampal pyramidal neurons were also immunopositive. The neuronal distribution of class III ADH resembled that of the vulnerable neurons in patients with hypoxic encephalopathy, which in view of the intense staining in the Purkinje cells, raises the possibility that this enzyme contributes to the hypoxia and cerebellar degeneration suffered by chronic alcoholics. Perivascular and subependymal astrocytes, which contribute to the maintenance of the cerebral cellular milieu and isolate the brain from the systemic circulation and cerebrospinal fluid, were also class III ADH positive. As the substrates of this enzyme include intrinsic toxic formaldehyde, inflammatory intermediate of 20-hydroxy-leukoteiene B4, and possibly ethanol, the distribution of class III ADH immunostaining indicates this enzyme contributes to the defence of the brain against degenerative processes. The finding that, unlike ependymal cells, subependymal astrocytes were class III ADH positive, suggests this enzyme may be useful for differentiating astrocytes and ependymal cells.
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PMID:Histological distribution of class III alcohol dehydrogenase in human brain. 1066 11


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