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

• Published in: Journal of the American Chemical Society 2004-08, Vol.126 (33), p.10278-10284
• Main Authors: Shin, Hyunshun, Cama, Evis, Christianson, David W
• Format: Article
• Language: English
• Subjects: 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; Biological and medical sciences; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Heptanoic Acids - chemical synthesis; Heptanoic Acids - chemistry; Kinetics; Mechanisms. Catalysis. Electron transfer. Models; Models, Molecular; Molecular biophysics; Physical chemistry in biology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja047788w

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 Å resolution. In the enzyme−inhibitor complex, the inhibitor aldehyde moiety is hydrated to form the gem-diol:  one hydroxyl group bridges the Mn2+ 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.