title: Structure of a glutathione conjugate bound to the active site of aldose reductase.
abstract: Aldose reductase (AR) is a monomeric NADPH-dependent oxidoreductase that catalyzes the reduction of aldehydes, ketones, and aldo-sugars. AR has been linked to the development of hyperglycemic injury and is a clinical target for the treatment of secondary diabetic complications. In addition to reducing glucose, AR is key regulator of cell signaling through it's reduction of aldehydes derived from lipoproteins and membrane phospholipids. AR catalyzes the reduction of glutathione conjugates of unsaturated aldehydes with higher catalytic efficiency than free aldehydes. The X-ray structure of human AR holoenzyme in complex with the glutathione analogue S-(1,2-dicarboxyethyl) glutathione (DCEG) was determined at a resolution of 1.94 A. The distal carboxylate group of DCEG's dicarboxyethyl moiety interacted with the conserved AR anion binding site residues Tyr48, His110, and Trp111. The bound DCEG's glutathione backbone adopted the low-energy Y-shape form. The C-terminal carboxylate of DCEG glutathione's glycine formed hydrogen bonds to Leu301 and Ser302, while the remaining interactions between DCEG and AR were hydrophobic, permitting significant flexibility of the AR and glutathione (GS) analogue interaction. The observed conformation and interactions of DCEG with AR were consistent with our previously published molecular dynamics model of glutathionyl-propanal binding to AR. The current structure identifies major interactions of glutathione conjugates with the AR active-site residues.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston 77555-0647, USA.
authors.forename: Ranvir
authors.initials: R
authors.lastname: Singh
authors.forename: Mark A
authors.initials: MA
authors.lastname: White
authors.forename: Kota V
authors.initials: KV
authors.lastname: Ramana
authors.forename: J Mark
authors.initials: JM
authors.lastname: Petrash
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watowich
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Satish K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000449:Aldehyde Reductase / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009249:NADP / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D009249:NADP; D000449:Aldehyde Reductase; D005978:Glutathione