Nω-Hydroxy-L-Arginine, an Intermediate in the L-Arginine to Nitric Oxide Pathway, Is a Strong Inhibitor of Liver and Macrophage Arginase

Abstract

Nω-Hydroxy-L-arginine (L-NOHA) is a potent inhibitor of the hydrolysis of L-arginine (L-Arg) to L-ornithine (L-Orn) catalyzed by purified bovine liver arginase (BLA). It appears as one of the most powerful arginase inhibitors reported so far (Ki = 150 μM). The other products of NO synthase are either without effect (NO2−, NO3−) or much weaker inhibitors (L-citrulline (L-Cit) and NO) of BLA. Products derived from a possible hydrolysis of L-Arg (L-Orn and urea) or of L-NOHA (L-Cit, hydroxyurea and hydroxylamine) are also inactive toward BLA at concentrations up to 2 mM. The configuration of L-NOHA is important as D-NOHA is much less active, and its free -COOH and α-NH2 functions are required for recognition of BLA. L-NOHA is also a potent inhibitor of the arginase activity of rat liver homogenates and of murine macrophages (IC50 of 150 and 450 μM, respectively). These remarkable properties of L-NOHA could play a role in the modulation of the biosynthesis of the biological mediator NO by increasing local L-Arg concentrations.