Structure of a glutathione conjugate bound to the active site of aldose reductase

Ranvir Singh, Mark White, Kota Ramana, J. Mark Petrash, Stanley Watowich, Aruni Bhatnagar, Satish Srivastava

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Aldose reductase (AR) is a monomeric NADPH-dependent oxidoreductase that catalyzes the reduction of aldehydes, ketones, and aldosugars. AR lias 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, AK 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 witli 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 Å. 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.

Original languageEnglish (US)
Pages (from-to)101-110
Number of pages10
JournalProteins: Structure, Function and Genetics
Volume64
Issue number1
DOIs
StatePublished - Jul 1 2006

Fingerprint

Aldehyde Reductase
Glutathione
Catalytic Domain
Aldehydes
S-(1,2-dicarboxyethyl)glutathione
Cell signaling
Holoenzymes
Molecular Models
Glutathione Reductase
Diabetes Complications
Molecular Dynamics Simulation
Ketones
NADP
Glycine
Lipoproteins
Anions
Conformations
Molecular dynamics
Hydrogen
Dynamic models

Keywords

  • Active site
  • Aldo-keto reductase
  • Competitive inhibitor
  • Crystal structure
  • Diabetic complications
  • Glutathiolation

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

Structure of a glutathione conjugate bound to the active site of aldose reductase. / Singh, Ranvir; White, Mark; Ramana, Kota; Petrash, J. Mark; Watowich, Stanley; Bhatnagar, Aruni; Srivastava, Satish.

In: Proteins: Structure, Function and Genetics, Vol. 64, No. 1, 01.07.2006, p. 101-110.

Research output: Contribution to journalArticle

Singh, Ranvir ; White, Mark ; Ramana, Kota ; Petrash, J. Mark ; Watowich, Stanley ; Bhatnagar, Aruni ; Srivastava, Satish. / Structure of a glutathione conjugate bound to the active site of aldose reductase. In: Proteins: Structure, Function and Genetics. 2006 ; Vol. 64, No. 1. pp. 101-110.
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