Arginases I and nor-NOHA complex
Rattus norvegicus (rat)
Arginases I and II require a binuclear manganese cluster for the hydrolysis of L-arginine to produce L-ornithine and urea. The arginase isozymes differ in terms of their tissue distribution, cellular localization, and metabolic function. Arginase plays an important role in regulating nitric oxide (NO) biosynthesis by reducing the levels of L-arginine available to NO synthase. Arginase inhibition can increase the substrate level for NO synthesis and accordingly enhance NO-dependent physiological processes, such as the smooth muscle relaxation required for sexual arousal. Therefore, arginase is a potential therapeutic target for the treatment of erectile dysfunction. The regulatory relationship between arginase and NO synthase is to some extent reciprocal, because the stable intermediate in NO biosynthesis is a competitive inhibitor of arginase. On the basis of the inhibitory properties of the substrate against arginase, a number of substrate analogs have been synthesized and evaluated.
The crystal structure shown here is rat arginase I complexed with substrate analogs, N-omega-hydroxy-nor-L-arginine (nor-NOHA). These structures of trimeric arginase show that the overall fold of arginase consists of a parallel, eight stranded beta-sheet flanked on both sides by multiple alpha-helices. In the complex with L-ornithine and urea (see xPSSS:1HQG), an L-ornithine hydroxide ion symmetrically bridges the binuclear manganese cluster located at the bottom of the active site cleft, whereas in the other complexes, the hydroxyl oxygen of the substrate analogues forms asymmetrical bridges. Comparisons of these structures reveal that the hydroxyl oxygen of the substrate analogs displaces the metal-bridging hydroxide ion and asymmetrically bridges the binuclear manganese cluster. These structures provide details in the reaction coordinate of arginase catalysis and significant insights about the structural determinants of tight binding inhibitors.
Protein Data Bank (PDB)
author: Aki Nagata