Structure and function of arginases.
The arginases catalyze the divalent cation dependent hydrolysis of L-arginine to produce L-ornithine and urea. Although traditionally considered in terms of its role as the final enzyme of the urea cycle, the enzyme is found in a variety of nonhepatic tissues. These findings suggest that the enzyme may have other functions in addition to its role in nitrogen metabolism. High-resolution crystal structures have been determined for recombinant rat liver (type I) arginase and for recombinant human kidney (type II) arginase, their variants, and complexes with products and inhibitors. Each identical subunit of the trimeric enzyme contains an active site that lies at the bottom of a 15 A deep cleft. The 2 essential Mn(II) ions are located at the bottom of this cleft, separated by approximately 3.3 A and bridged by oxygens derived from 2 aspartic acid residues and a solvent-derived hydroxide. This metal bridging hydroxide is proposed to be the nucleophile that attacks the guanidinium carbon of substrate arginine. On the basis of this proposed mechanism, boronic acid inhibitors of the enzyme have been synthesized and characterized kinetically and structurally. These inhibitors display slow-onset inhibition at the pH optimum of the enzyme, and are found as tetrahedral species at the active site, as determined by X-ray diffraction. The potent inhibition of arginases I and II by these compounds has not only delineated key enzyme-substrate interactions, but has also led to a greater understanding of the role of arginase in nonhepatic tissues.
Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA. deash@temple.edu
David E
DE
Ash
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008670:Metals / Q000378:metabolism; D013329:Structure-Activity Relationship
D001897:Boronic Acids; D004791:Enzyme Inhibitors; D008670:Metals; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D001119:Arginase