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Novel NADPH-binding domain revealed by the crystal structure of aldose reductase

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Abstract

ALDOSE reductase is the first enzyme in the polyol pathway and catalyses the NADPH-dependent reduction of D-glucose to D-sorbitol. Under normal physiological conditions aldose reductase participates in osmoregulation1, but under hyperglycaemic conditions it contributes to the onset and development of severe complications in diabetes2. Here we present the crystal structure of pig lens aldose reductase refined to an R-factor of 0.232 at 2.5-Å resolution. It exhibits a single domain folded in an eight-stranded parallel α/β barrel, similar to that in triose phosphate isomerase3 and a score of other enzymes. Hence, aldose reductase does not possess the expected canonical dinucleotide-binding domain4. Crystallographic analysis of the binding of 2′-monophospho-adenosine-5′-diphosphoribose, which competitively inhibits NADPH binding reveals that it binds into a cleft located at the C-terminal end of the strands of the α/β barrel. This represents a new type of binding for nicotinamide adenine dinucleotide coenzymes.

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Author notes

  1. D. Moras: To whom correspondence should be addressed.

Authors and Affiliations

  1. Laboratoire de Cristallographie Biologique, Institut de Biologie Moleculaire et Cellulaire du CNRS, 15 rue R. Descartes, 67084, Strasbourg Cedex, France

    J.-M. Rondeau, F. Tête-Favier, A Podjarny & D. Moras

  2. Biostructure SA, Les Algorithmes, Batiment Euclide, Pare d'lnnovation, 67400, Illkirch-Graffenstaden, France

    J.-M. Rondeau & F. Tête-Favier

  3. Laboratoire de Chimie OrganiqueBiologique, Institut de Chimie, Universite Louis Pasteur, 4 rue B. Pascal, 67008, Strasbourg Cedex, France

    J.-M. Reymann, P. Barth & J.-F. Biellmann

Authors
  1. J.-M. Rondeau
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  2. F. Tête-Favier
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  3. A Podjarny
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  4. J.-M. Reymann
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  5. P. Barth
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  6. J.-F. Biellmann
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  7. D. Moras
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Rondeau, JM., Tête-Favier, F., Podjarny, A. et al. Novel NADPH-binding domain revealed by the crystal structure of aldose reductase. Nature 355, 469–472 (1992). https://doi.org/10.1038/355469a0

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