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Research article

Kinetic characterization and regulation of the human retinaldehyde dehydrogenase 2 enzyme during production of retinoic acid

Yehuda Shabtai, Halim Jubran, Taher Nassar, Joseph Hirschberg, Abraham Fainsod
Biochemical Journal May 11, 2016, 473 (10) 1423-1431; DOI: 10.1042/BCJ20160101
Yehuda Shabtai
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel–Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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Halim Jubran
Department of Genetics, Alexander Silberman Institute of Life Sciences, Faculty of Science, Hebrew University of Jerusalem, Jerusalem, Israel
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Taher Nassar
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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Joseph Hirschberg
Department of Genetics, Alexander Silberman Institute of Life Sciences, Faculty of Science, Hebrew University of Jerusalem, Jerusalem, Israel
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Abraham Fainsod
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel–Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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  • For correspondence: abrahamf@ekmd.huji.ac.il
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Abstract

Retinoic acid (RA) is an important regulator of embryogenesis and tissue homoeostasis. Perturbation of RA signalling causes developmental disorders, osteoarthritis, schizophrenia and several types of tumours. RA is produced by oxidation of retinaldehyde from vitamin A. The main enzyme producing RA in the early embryo is retinaldehyde dehydrogenase 2 (RALDH2, ALDH1A2). In the present study we describe in depth the kinetic properties and regulation of the human RALDH2 (hRALDH2) enzyme. We show that this enzyme produces RA using in vivo and in vitro assays. We studied the naturally occurring all-trans-, 9-cis- and 13-cis-retinaldehyde isomers as substrates of hRALDH2. Based on the values measured for the Michaelis–Menten constant Km and the maximal rate Vmax, in vitro hRALDH2 displays the same catalytic efficiency for their oxidation. We characterized two known inhibitors of the vertebrate RALDH2 and determined their kinetic parameters on hRALDH2. In addition, RA was studied as a possible inhibitor of hRALDH2 and a regulator of its activity. We show that hRALDH2 is not inhibited by its oxidation product, all-trans-RA, suggesting the absence of a negative feedback regulatory loop. Expression of the Raldh2 gene is known to be regulated by RA itself, suggesting that the main regulation of the hRALDH2 activity level is transcriptional.

  • ALDH1A2
  • enzyme kinetics
  • retinoic acid signalling
  • retinaldehyde dehydrogenase
  • vitamin A metabolism
  • Abbreviations

    9cRA,
    9-cis-retinoic acid;
    13cRA,
    13-cis-retinoic acid;
    ALDH,
    aldehyde dehydrogenase;
    atRA,
    all-trans-retinoic acid;
    DEAB,
    4-diethylaminobenzaldehyde;
    FASD,
    fetal alcohol spectrum disorder;
    hRALDH2,
    human RALDH2;
    qPCR,
    quantitative real-time PCR;
    RA,
    retinoic acid;
    RAL,
    retinaldehyde;
    RALDH,
    retinaldehyde dehydrogenase;
    RAR,
    retinoic acid receptor;
    RXR,
    retinoid X receptor
    • © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
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    May 2016

    Volume: 473 Issue: 10

    Biochemical Journal: 473 (10)
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    Kinetic characterization and regulation of the human retinaldehyde dehydrogenase 2 enzyme during production of retinoic acid
    Yehuda Shabtai, Halim Jubran, Taher Nassar, Joseph Hirschberg, Abraham Fainsod
    Biochemical Journal May 2016, 473 (10) 1423-1431; DOI: 10.1042/BCJ20160101
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    Kinetic characterization and regulation of the human retinaldehyde dehydrogenase 2 enzyme during production of retinoic acid
    Yehuda Shabtai, Halim Jubran, Taher Nassar, Joseph Hirschberg, Abraham Fainsod
    Biochemical Journal May 2016, 473 (10) 1423-1431; DOI: 10.1042/BCJ20160101

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    Keywords

    ALDH1A2
    enzyme kinetics
    retinoic acid signalling
    retinaldehyde dehydrogenase
    vitamin A metabolism

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