Aldo-keto reductases from the AKR1B subfamily: Retinoid specificity and control of cellular retinoic acid levels

F. Xavier Ruiz, Oriol Gallego, Albert Ardèvol, Armando Moro, Marta Domínguez, Susana Alvarez, Rosana Alvarez, Angel R. de Lera, Carme Rovira, Ignacio Fita, Xavier Parés, Jaume Farrés

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56 Citations (Scopus)

Abstract

NADP(H)-dependent cytosolic aldo-keto reductases (AKRs) have been added to the group of enzymes which contribute to oxidoreductive conversions of retinoids. Recently, we found that two members from the AKR1B subfamily (AKR1B1 and AKRB10) were active in the reduction of all-trans- and 9-cis-retinaldehyde, with Km values in the micromolar range, but with very different kcat values. With all-trans-retinaldehyde, AKR1B10 shows a much higher kcat value than AKR1B1 (18 min-1 vs. 0.37 min-1) and a catalytic efficiency comparable to that of the best retinaldehyde reductases. Structural, molecular dynamics and site-directed mutagenesis studies on AKR1B1 and AKR1B10 point that subtle differences at the entrance of their retinoid-binding site, especially at position 125, are determinant for the all-trans-retinaldehyde specificity of AKR1B10. Substitutions in the retinoid cyclohexene ring, analyzed here further, also influence such specificity. Overall it is suggested that the rate-limiting step in the reaction mechanism with retinaldehyde differs between AKR1B1 and AKR1B10. In addition, we demonstrate here that enzymatic activity of AKR1B1 and AKR1B10 lowers all-trans- and 9-cis-retinoic acid-dependent trans-activation in living cells, indicating that both enzymes may contribute to pre-receptor regulation of retinoic acid and retinoid X nuclear receptors. This result supports that overexpression of AKR1B10 in cancer (an updated review on this topic is included) may contribute to dedifferentiation and tumor development. © 2008 Elsevier Ireland Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)171-177
JournalChemico-Biological Interactions
Volume178
DOIs
Publication statusPublished - 16 Mar 2009

Keywords

  • Aldo-keto reductases
  • Aldose reductase
  • Cancer
  • Protein structure
  • Retinoic acid
  • Tumor marker

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