Design of Amino Acid Aldehydes as Transition-State Analogue Inhibitors of Arginase

J Am Chem Soc. 2004 Aug 25;126(33):10278-84. doi: 10.1021/ja047788w.

Abstract

Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. Chiral L-amino acids bearing aldehyde side chains have been synthesized in which the electrophilic aldehyde C=O bond is isosteric with the C=N bond of L-arginine. This substitution is intended to facilitate nucleophilic attack by the metal-bridging hydroxide ion upon binding to the arginase active site. Syntheses of the amino acid aldehydes have been accomplished by reduction, oxidation, and Wittig-type reaction with a commercially available derivative of L-glutamic acid. Amino acid aldehydes exhibit inhibition in the micromolar range, and the X-ray crystal structure of arginase I complexed with one of these inhibitors, (S)-2-amino-7-oxoheptanoic acid, has been determined at 2.2 A resolution. In the enzyme-inhibitor complex, the inhibitor aldehyde moiety is hydrated to form the gem-diol: one hydroxyl group bridges the Mn(2+)(2) cluster and donates a hydrogen bond to D128, and the second hydroxyl group donates a hydrogen bond to E277. The binding mode of the neutral gem-diol may mimic the binding of the neutral tetrahedral intermediate and its flanking transition states in arginase catalysis.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldehydes / chemical synthesis
  • Aldehydes / chemistry*
  • Aldehydes / metabolism
  • Aldehydes / pharmacology
  • Amino Acids / chemical synthesis
  • Amino Acids / chemistry*
  • Amino Acids / metabolism
  • Amino Acids / pharmacology
  • Arginase / antagonists & inhibitors*
  • Arginase / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Heptanoic Acids / chemical synthesis
  • Heptanoic Acids / chemistry
  • Kinetics
  • Models, Molecular

Substances

  • Aldehydes
  • Amino Acids
  • Enzyme Inhibitors
  • Heptanoic Acids
  • Arginase