title: Novel NADPH-binding domain revealed by the crystal structure of aldose reductase.
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 osmoregulation, but under hyperglycaemic conditions it contributes to the onset and development of severe complications in diabetes. Here we present the crystal structure of pig lens aldose reductase refined to an R-factor of 0.232 at 2.5-A resolution. It exhibits a single domain folded in an eight-stranded parallel alpha/beta barrel, similar to that in triose phosphate isomerase and a score of other enzymes. Hence, aldose reductase does not possess the expected canonical dinucleotide-binding domain. 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 alpha/beta barrel. This represents a new type of binding for nicotinamide adenine dinucleotide coenzymes.
authors.affiliation: Laboratoire de Cristallographie Biologique, Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Rondeau
authors.forename: F
authors.initials: F
authors.lastname: Tête-Favier
authors.forename: A
authors.initials: A
authors.lastname: Podjarny
authors.forename: J M
authors.initials: JM
authors.lastname: Reymann
authors.forename: P
authors.initials: P
authors.lastname: Barth
authors.forename: J F
authors.initials: JF
authors.lastname: Biellmann
authors.forename: D
authors.initials: D
authors.lastname: Moras
mesh_terms: D000449:Aldehyde Reductase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D046911:Macromolecular Substances; D008958:Models, Molecular; D009249:NADP / Q000378:metabolism*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D046911:Macromolecular Substances; D009249:NADP; D000449:Aldehyde Reductase