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Alcohol Dehydrogenases

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Hans Jörnvall – One of the best experts on this subject based on the ideXlab platform.

  • origin and evolution of medium chain Alcohol Dehydrogenases
    Chemico-Biological Interactions, 2013
    Co-Authors: Hans Jörnvall, Bengt Persson, Ella Cederlund, Joel Hedlund, Tomas Bergman, Yvonne Kallberg
    Abstract:

    Different lines of Alcohol Dehydrogenases (ADHs) have separate superfamily origins, already recognized but now extended and re-evaluated by re-screening of the latest databank update. The short-chain form (SDR) is still the superfamily with most abundant occurrence, most multiple divergence, most prokaryotic emphasis, and most non-complicated architecture. This pattern is compatible with an early appearance at the time of the emergence of prokaryotic cellular life. The medium-chain form (MDR) is also old but second in terms of all the parameters above, and therefore compatible with a second emergence. However, this step appears seemingly earlier than previously considered, and may indicate sub-stages of early emergences at the increased resolution available from the now greater number of data entries. The Zn-MDR origin constitutes a third stage, possibly compatible with the transition to oxidative conditions on earth. Within all these three lines, repeated enzymogeneses gave the present divergence. MDR-ADH origin(s), at a fourth stage, may also be further resolved in multiple or extended modes, but the classical liver MDR-ADH of the liver type can still be traced to a gene duplication ~550 MYA (million years ago), at the early vertebrate radiation, compatible with the post-eon-shift, “Cambrian explosion”. Classes and isozymes correspond to subsequent and recent duplicatory events, respectively. They illustrate a peculiar pattern with functional and emerging evolutionary distinctions between parent and emerging lines, suggesting a parallelism between duplicatory and mutational events, now also visible at separate sub-stages. Combined, all forms show distinctive patterns at different levels and illustrate correlations with global events. They further show that simple molecular observations on patterns, multiplicities and occurrence give much information, suggesting common divergence rules not much disturbed by horizontal gene transfers after the initial origins.

  • characterization of new medium chain Alcohol Dehydrogenases adds resolution to duplications of the class i iii and the sub class i genes
    Chemico-Biological Interactions, 2011
    Co-Authors: Ella Cederlund, Jawed Shafqat, Lars Hjelmqvist, Bengt Persson, Annika Norin, Joel Hedlund, Andreas P Jonsson, Wingming Keung, Hans Jörnvall
    Abstract:

    Four additional variants of Alcohol and aldehyde Dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR Alcohol Dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver Alcohol Dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver Alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed.

  • mycothiol dependent formaldehyde dehydrogenase a prokaryotic medium chain dehydrogenase reductase phylogenetically links different eukaroytic Alcohol Dehydrogenases primary structure conformational modelling and functional correlations
    FEBS Journal, 1997
    Co-Authors: Annika Norin, Bengt Persson, Peter W Van Ophem, Sander R Piersma, Johannis A Duine, Hans Jörnvall
    Abstract:

    Prokaryotic mycothiol-dependent formaldehyde dehydrogenase has been structurally characterized by peptide analysis of the 360-residue protein chain and by molecular modelling and functional correlation with the conformational properties of zinc-containing Alcohol Dehydrogenases. The structure is found to be a divergent medium-chain dehydrogenase/reductase (MDR), at a phylogenetic position intermediate between the cluster of dimeric Alcohol Dehydrogenases of all classes (including the human forms), and several tetrameric reductases/Dehydrogenases. Molecular modelling and functionally important residues suggest a fold of the mycothiol-dependent formaldehyde dehydrogenase related overall to that of MDR Alcohol Dehydrogenases, with the presence of the catalytic and structural zinc atoms, but otherwise much altered active-site relationships compatible with the different substrate specificity, and an altered loop structure compatible with differences in the quaternary structure. Residues typical of glutathione binding in class-III Alcohol dehydrogenase are not present, consistent with that the mycothiol factor is not closely similar to glutathione. The molecular architecture is different from that of the ‘constant’ Alcohol Dehydrogenases (of class-III type) and the ‘variable’ Alcohol Dehydrogenases (of class-I and class-II types), further supporting the unique structure of mycothiol-dependent formaldehyde dehydrogenase. Borders of internal chain-length differences between this and other MDR enzymes coincide in different combinations, supporting the concept of limited changes in loop regions within this whole family of proteins.

Vicente Gotor – One of the best experts on this subject based on the ideXlab platform.

  • expanding the scope of Alcohol Dehydrogenases towards bulkier substrates stereo and enantiopreference for α α dihalogenated ketones
    Chemcatchem, 2014
    Co-Authors: Kinga Kedziora, Iván Lavandera, Wolfgang Kroutil, Fabricio R Bisogno, Vicente Gotorfernandez, Jose Montejobernardo, Santiago Garciagranda, Vicente Gotor
    Abstract:

    Alcohol Dehydrogenases (ADHs) were identified as suitable enzymes for the reduction of the corresponding α,α-dihalogenated ketones, obtaining optically pure β,β-dichloro- or β,β-dibromohydrins with excellent conversions and enantiomeric excess. Among the different biocatalysts tested, ADHs from Rhodococcus ruber (ADH-A), Ralstonia sp. (RasADH), Lactobacillus brevis (LBADH), and PR2ADH proved to be the most efficient ones in terms of activity and stereoselectivity. In a further study, two racemic α-substituted ketones, namely α-bromo- α-chloro- and α-chloro-α-fluoroacetophenone were investigated to obtain one of the four possible diastereoisomers through a dynamic kinetic process. In the case of the brominated derivative, only the (1R)-enantiomer was obtained by using ADH-A, although with moderate diastereomeric excess (>99 % ee, 63 % de), whereas the fluorinated ketone exhibited a lower stereoselectivity (up to 45 % de).

  • synthesis of enantiopure fluorohydrins using Alcohol Dehydrogenases at high substrate concentrations
    ChemInform, 2013
    Co-Authors: Wioleta Borzecka, Iván Lavandera, Vicente Gotor
    Abstract:

    It is shown that different Alcohol Dehydrogenases can be used to synthesize both Alcohol antipodes in an enantiopure form by reduction of α-fluoro ketones.

  • synthesis of enantiopure fluorohydrins using Alcohol Dehydrogenases at high substrate concentrations
    Journal of Organic Chemistry, 2013
    Co-Authors: Wioleta Borzecka, Iván Lavandera, Vicente Gotor
    Abstract:

    The use of purified and overexpressed Alcohol Dehydrogenases to synthesize enantiopure fluorinated Alcohols is shown. When the bioreductions were performed with ADH-A from Rhodococcus ruber overexpressed in E. coli, no external cofactor was necessary to obtain the enantiopure (R)-derivatives. Employing Lactobacillus brevis ADH, it was possible to achieve the synthesis of enantiopure (S)-fluorohydrins at a 0.5 M substrate concentration. Furthermore, due to the activated character of these substrates, a huge excess of the hydrogen donor was not necessary.

Bengt Persson – One of the best experts on this subject based on the ideXlab platform.

  • origin and evolution of medium chain Alcohol Dehydrogenases
    Chemico-Biological Interactions, 2013
    Co-Authors: Hans Jörnvall, Bengt Persson, Ella Cederlund, Joel Hedlund, Tomas Bergman, Yvonne Kallberg
    Abstract:

    Different lines of Alcohol Dehydrogenases (ADHs) have separate superfamily origins, already recognized but now extended and re-evaluated by re-screening of the latest databank update. The short-chain form (SDR) is still the superfamily with most abundant occurrence, most multiple divergence, most prokaryotic emphasis, and most non-complicated architecture. This pattern is compatible with an early appearance at the time of the emergence of prokaryotic cellular life. The medium-chain form (MDR) is also old but second in terms of all the parameters above, and therefore compatible with a second emergence. However, this step appears seemingly earlier than previously considered, and may indicate sub-stages of early emergences at the increased resolution available from the now greater number of data entries. The Zn-MDR origin constitutes a third stage, possibly compatible with the transition to oxidative conditions on earth. Within all these three lines, repeated enzymogeneses gave the present divergence. MDR-ADH origin(s), at a fourth stage, may also be further resolved in multiple or extended modes, but the classical liver MDR-ADH of the liver type can still be traced to a gene duplication ~550 MYA (million years ago), at the early vertebrate radiation, compatible with the post-eon-shift, “Cambrian explosion”. Classes and isozymes correspond to subsequent and recent duplicatory events, respectively. They illustrate a peculiar pattern with functional and emerging evolutionary distinctions between parent and emerging lines, suggesting a parallelism between duplicatory and mutational events, now also visible at separate sub-stages. Combined, all forms show distinctive patterns at different levels and illustrate correlations with global events. They further show that simple molecular observations on patterns, multiplicities and occurrence give much information, suggesting common divergence rules not much disturbed by horizontal gene transfers after the initial origins.

  • characterization of new medium chain Alcohol Dehydrogenases adds resolution to duplications of the class i iii and the sub class i genes
    Chemico-Biological Interactions, 2011
    Co-Authors: Ella Cederlund, Jawed Shafqat, Lars Hjelmqvist, Bengt Persson, Annika Norin, Joel Hedlund, Andreas P Jonsson, Wingming Keung, Hans Jörnvall
    Abstract:

    Four additional variants of Alcohol and aldehyde Dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR Alcohol Dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver Alcohol Dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver Alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed.

  • mycothiol dependent formaldehyde dehydrogenase a prokaryotic medium chain dehydrogenase reductase phylogenetically links different eukaroytic Alcohol Dehydrogenases primary structure conformational modelling and functional correlations
    FEBS Journal, 1997
    Co-Authors: Annika Norin, Bengt Persson, Peter W Van Ophem, Sander R Piersma, Johannis A Duine, Hans Jörnvall
    Abstract:

    Prokaryotic mycothiol-dependent formaldehyde dehydrogenase has been structurally characterized by peptide analysis of the 360-residue protein chain and by molecular modelling and functional correlation with the conformational properties of zinc-containing Alcohol Dehydrogenases. The structure is found to be a divergent medium-chain dehydrogenase/reductase (MDR), at a phylogenetic position intermediate between the cluster of dimeric Alcohol Dehydrogenases of all classes (including the human forms), and several tetrameric reductases/Dehydrogenases. Molecular modelling and functionally important residues suggest a fold of the mycothiol-dependent formaldehyde dehydrogenase related overall to that of MDR Alcohol Dehydrogenases, with the presence of the catalytic and structural zinc atoms, but otherwise much altered active-site relationships compatible with the different substrate specificity, and an altered loop structure compatible with differences in the quaternary structure. Residues typical of glutathione binding in class-III Alcohol dehydrogenase are not present, consistent with that the mycothiol factor is not closely similar to glutathione. The molecular architecture is different from that of the ‘constant’ Alcohol Dehydrogenases (of class-III type) and the ‘variable’ Alcohol Dehydrogenases (of class-I and class-II types), further supporting the unique structure of mycothiol-dependent formaldehyde dehydrogenase. Borders of internal chain-length differences between this and other MDR enzymes coincide in different combinations, supporting the concept of limited changes in loop regions within this whole family of proteins.

Kazunobu Matsushita – One of the best experts on this subject based on the ideXlab platform.

  • molecular cloning and characterization of two inducible nad adh genes encoding nad dependent Alcohol Dehydrogenases from acetobacter pasteurianus sku1108
    Journal of Bioscience and Bioengineering, 2011
    Co-Authors: Uraiwan Masud, Kazunobu Matsushita, Gunjana Theeragool
    Abstract:

    Abstract The cytosolic NAD + -dependent Alcohol Dehydrogenases (NAD + -ADHs) are induced in the quinoprotein ADH-(PQQ-ADH) defective Acetobacter pasteurianus SKU1108 mutant during growth in an ethanol medium. The a dhI and adhII genes, which encode NAD + -ADH I and ADH II, respectively, of this strain have been cloned and characterized. Sequence analyses have revealed that the adhI gene consists of 1029 bp coding for 342 amino acids, which share 99.71% identity with the same protein from A. pasteurianus IFO 3283. Conversely, the adhII gene is composed of 762 bp encoding for a polypeptide of 253 amino acids, which exhibit 99.60% identity with the A. pasteurianus IFO 3283 protein. ADH I is a member of the group I Zn-dependent long-chain ADHs, while the ADH II belongs to the group II short-chain dehydrogenase/reductase NAD + -ADHs. The NAD + – adh gene disruptants exhibited a growth reduction when grown in an ethanol medium. In Escherichia coli , ethanol induced adhI and adhII promoter activities by approximately 1.5 and 2.0 times, respectively, and the promoter activity of the adhII gene exceeded that of the adhI gene by approximately 3.5 times. The possible promoter regions of the adhI and adhII genes are located at approximately 81–105 bp and 74–92 bp, respectively, from their respective ATG start codons. Their repressor regions might be located in proximity to these promoters and may repress gene expression in the wild-type, where the membrane-bound ADH effectively functions.

  • Characterization of thermotolerant Acetobacter pasteurianus strains and their quinoprotein Alcohol Dehydrogenases.
    Applied microbiology and biotechnology, 2009
    Co-Authors: Watchara Kanchanarach, Gunjana Theeragool, Toshiharu Yakushi, Hirohide Toyama, Osao Adachi, Kazunobu Matsushita
    Abstract:

    We isolated several thermotolerant Acetobacter species of which MSU10 strain, identified as Acetobacter pasteurianus, could grow well on agar plates at 41°C, tolerate to 1.5% acetic acid or 4% ethanol at 39°C, similarly seen with A. pasteurianus SKU1108 previously isolated. The MSU10 strain showed higher acetic acid productivity in a medium containing 6% ethanol at 37°C than SKU1108 while SKU1108 strain could accumulate more acetic acid in a medium supplemented with 4–5% ethanol at the same temperature. The fermentation ability at 37°C of these thermotolerant strains was superior to that of mesophilic A. pasteurianus IFO3191 strain having weak growth and very delayed acetic acid production at 37°C even at 4% ethanol. Alcohol Dehydrogenases (ADHs) were purified from MSU10, SKU1108, and IFO3191 strains, and their properties were compared related to the thermotolerance. ADH of the thermotolerant strains had a little higher optimal temperature and heat stability than that of mesophilic IFO3191. More critically, ADHs from MSU10 and SKU1108 strains exhibited a higher resistance to ethanol and acetic acid than IFO3191 enzyme at elevated temperature. Furthermore, in this study, the ADH genes were cloned, and the amino acid sequences of ADH subunit I, subunit II, and subunit III were compared. The difference in the amino acid residues could be seen, seemingly related to the thermotolerance, between MSU10 or SKU1108 ADH and IFO 3191 ADH.

  • quinohemoprotein Alcohol Dehydrogenases structure function and physiology
    Archives of Biochemistry and Biophysics, 2004
    Co-Authors: Hirohide Toyama, Kazunobu Matsushita, Osao Adachi, Scott F Mathews
    Abstract:

    Quino(hemo)protein Alcohol Dehydrogenases (ADH) that have pyrroloquinoline quinone (PQQ) as the prosthetic group are classified into 3 groups, types I, II, and III. Type I ADH is a simple quinoprotein having PQQ as the only prosthetic group, while type II and type III ADHs are quinohemoprotein having heme c as well as PQQ in the catalytic polypeptide. Type II ADH is a soluble periplasmic enzyme and is widely distributed in Proteobacteria such as Pseudomonas, Ralstonia, Comamonas, etc. In contrast, type III ADH is a membrane-bound enzyme working on the periplasmic surface solely in acetic acid bacteria. It consists of three subunits that comprise a quinohemoprotein catalytic subunit, a triheme cytochrome c subunit, and a third subunit of unknown function. The catalytic subunits of all the quino(hemo)protein ADHs have a common structural motif, a quinoprotein-specific superbarrel domain, where PQQ is deeply embedded in the center. In addition, in the type II and type III ADHs this subunit contains a unique heme c domain. Various type II ADHs each have a unique substrate specificity, accepting a wide variety of Alcohols, as is discussed on the basis of recent X-ray crystallographic analyses. Electron transfer within both type II and III ADHs is discussed in terms of the intramolecular reaction from PQQ to heme c and also from heme to heme, and in terms of the intermolecular reaction with azurin and ubiquinone, respectively. Unique physiological functions of both types of quinohemoprotein ADHs are also discussed.

Bryce V. Plapp – One of the best experts on this subject based on the ideXlab platform.

  • activity of yeast Alcohol Dehydrogenases on benzyl Alcohols and benzaldehydes characterization of adh1 from saccharomyces carlsbergensis and transition state analysis
    Chemico-Biological Interactions, 2009
    Co-Authors: Suresh Pal, Doohong Park, Bryce V. Plapp
    Abstract:

    Abstract The substrate specificities of yeast Alcohol Dehydrogenases I and II from Saccharomyces cerevisiae ( Sce ADH1 and Sce ADH2) and Saccharomyces carlsbergensis ( Scb ADH1) were studied. For this work, the gene for the S. carlsbergensis ADH1 was cloned, sequenced and expressed. The amino acid sequence of Scb ADH1 differs at four positions as compared to Sce ADH1, including substitutions of two glutamine residues with glutamic acid residues, and has the same sequence as the commercial yeast enzyme, which apparently is prepared from S. carlsbergensis . The electrophoretic mobilities of Scb ADH1, Sce ADH2 and commercial ADH are similar. The kinetics and specificities of Scb ADH1 and Sce ADH1 acting on branched, long-chain and benzyl Alcohols are very similar, but the catalytic efficiency of Sce ADH2 is about 10–100-fold higher on these substrates. A three-dimensional structure of Sce ADH1 shows that the substrate binding pocket has Met-270, whereas Sce ADH2 has Leu-270, which allows larger substrates to bind. The reduction of a series of p -substituted benzaldehydes catalyzed by Sce ADH2 is significantly enhanced by electron-withdrawing groups, whereas the oxidation of p -substituted aromatic Alcohols may be only slightly affected by the substituents. The substituent effects on catalysis generally reflect the effects on the equilibrium constant for the reaction, where electron-withdrawing substituents favor Alcohol. The results are consistent with a transition state that is electronically similar to the Alcohol, supporting previous results obtained with commercial yeast ADH.

  • formamides mimic aldehydes and inhibit liver Alcohol Dehydrogenases and ethanol metabolism
    Journal of Biological Chemistry, 2003
    Co-Authors: Thulasiram H Venkataramaiah, Bryce V. Plapp
    Abstract:

    Formamides are unreactive analogues of the aldehyde substrates of Alcohol Dehydrogenases and are useful for structure-function studies and for specific inhibition of Alcohol metabolism. They bind to the enzyme-NADH complex and are uncompetitive inhibitors against varied concentrations of Alcohol. Fourteen new branched chain and chiral formamides were prepared and tested as inhibitors of purified Class I liver Alcohol Dehydrogenases: horse (EqADH E), human (HsADH1C*2), and mouse (MmADH1). In general, larger, substituted formamides, such as N-1-ethylheptylformamide, are better inhibitors of HsADH1C*2 and MmADH1 than of EqADH, reflecting a few differences in amino acid residues that change the sizes of the active sites. In contrast, the linear, alkyl (n-propyl and n-butyl) formamides are better inhibitors of EqADH and MmADH1 than of HsADH1C*2, probably because water disrupts van der Waals interactions. These enzymes are also inhibited strongly by sulfoxides and 4-substituted pyrazoles. The structure of EqADH complexed with NADH and (R)-N-1-methylhexylformamide was determined by x-ray crystallography at 1.6 A resolution. The structure resembles the expected Michaelis complex with NADH and aldehyde, and shows for the first time that the reduced nicotinamide ring of NADH is puckered, as predicted for the transition state for hydride transfer. Metabolism of ethanol in mice was inhibited by several formamides. The data were fitted with kinetic simulation to a mechanism that describes the non-linear progress curves and yields estimates of the in vivo inhibition constants and the rate constants for elimination of inhibitors. Some small formamides, such as N-isopropylformamide, may be useful inhibitors in vivo.

  • Uncompetitive Inhibitors of Alcohol Dehydrogenases
    Advances in experimental medicine and biology, 1999
    Co-Authors: Bryce V. Plapp, Vijay K. Chadha, Kevin G. Leidal, Heeyeong Cho, Michael Scholze, John F. Schindler, Kristine B. Berst, S. Ramaswamy
    Abstract:

    Selective inhibitors of Alcohol Dehydrogenases could be useful for prevention of poisoning due to metabolism of Alcohols, such as methanol or ethylene glycol, that lead to toxic products (Jacobsen and McMartin, 1997). Good inhibitors could also be used to study the physiological functions of the various isoenzymes of Alcohol dehydrogenase and for therapeutic intervention after the metabolic roles of the enzymes are established. Although 4-methylpyrazole is a potent inhibitor of some of the liver Alcohol Dehydrogenases, it is not very effective against all of the human isoenzymes, and it is a competitive inhiinhibitor against Alcohol, which makes it less effective when the concentration of substrate Alcohol is increased. Thus, we have been designing, synthesizing, and evaluating potentially specific inhibitors that are uncompetitive against varied concentrations of Alcohols. The research has led to some selective inhibitors of human Alcohol Dehydrogenases and structure- function information about the specificities of the enzymes.