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

@article{Rondeau1992NovelND,
  title={Novel NADPH-binding domain revealed by the crystal structure of aldose reductase},
  author={J. M. Rondeau and Fr{\'e}d{\'e}rique T{\^e}te-Favier and Alberto D. Podjarny and Jean Michel Reymann and Patrick Barth and Jean François Biellmann and Dino Moras},
  journal={Nature},
  year={1992},
  volume={355},
  pages={469-472}
}
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… Expand
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The crystal structure of the aldose reductase.NADPH binary complex.
TLDR
The crystal structure revealed that the enzyme is a beta/alpha-barrel with the coenzyme-binding domain located at the carboxyl-terminal end of the parallel strands of the barrel, and NADPH is bound to aldose reductase in an unusual manner, more similar to FAD- rather than NAD(P)-dependent oxidoreductases. Expand
Crystal structure of yeast xylose reductase in complex with a novel NADP‐DTT adduct provides insights into substrate recognition and catalysis
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The crystal structure of the complex reveals a covalent linkage between the C4N atom of the nicotinamide ring of the cosubstrate and the S1 sulfur atom of DTT and provides the first structural evidence for a protein mediated NADP–low‐molecular‐mass thiol adduct. Expand
The structure of Apo R268A human aldose reductase: hinges and latches that control the kinetic mechanism.
TLDR
The R268A mutant enzyme has similar kinetic parameters to the wild-type enzyme for aldehyde substrates, yet has greatly reduced affinity for the nucleotide substrate which greatly facilitates its crystallization in the apoenzyme form. Expand
Structure of a glutathione conjugate bound to the active site of aldose reductase
TLDR
The observed conformation and interactions of DCEG with AR were consistent with the previously published molecular dynamics model of glutathionyl–propanal binding to AR, and the current structure identifies major interactions of glutATHione conjugates with the AR active‐site residues. Expand
An anion binding site in human aldose reductase: mechanistic implications for the binding of citrate, cacodylate, and glucose 6-phosphate.
TLDR
The location of citrate binding in the active site leads to a plausible catalytic mechanism for aldose reductase, as well as confirmatory evidence by both kinetic and crystallographic experiments. Expand
Studies on Human Aldose Reductase.
TLDR
The present study shows that mutation of Arg-268 to methionine results in a 36-fold increase in K and 205-fold increased in K for NADPH, but little change inK for DL-glyceraldehyde or in the k of the reaction. Expand
Substrate specificity of human aldose reductase: identification of 4-hydroxynonenal as an endogenous substrate.
TLDR
Analysis of the binding of NADPH by fluorescence quenching techniques indicates that aldose reductase exhibits higher affinity for NADPH than NADP, suggesting that this enzyme is normally primed for reductive metabolism. Expand
Mechanism of human aldehyde reductase: characterization of the active site pocket.
TLDR
Dissociation constants and spectroscopic and fluorimetric properties of nucleotide complexes with various mutants suggest that, in addition to Tyr49 and His112, Lys79 plays a hitherto unappreciated role in nucleotide binding. Expand
Structure of human aldose reductase holoenzyme in complex with Statil: An approach to structure‐based inhibitor design of the enzyme
TLDR
Based on the model of the ternary complex, the program GRID was used in an attempt to design novel potential inhibitors of human aldose reductase with enhanced binding energies of the complex. Expand
The crystal structure of the GCY1 protein from S. cerevisiae suggests a divergent aldo-keto reductase catalytic mechanism.
TLDR
The crystal structure of the GCY1 gene product from Saccharomyces cerevisiae has been determined to 2.5 A and is being refined and it is revealed that the active site surface is somewhat flat when compared with the other aldo-keto reductase structures, possibly accommodating larger substrates. Expand
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