N omega-hydroxyl-L-arginine, an intermediate in the L-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase.
N omega-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 microM). 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 alpha-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 microM, 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.
Boucher
J L
JL
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris V, CNRS URA 400, France.
Custot
J
J
Vadon
S
S
Delaforge
M
M
Lepoivre
M
M
Tenu
J P
JP
Yapo
A
A
Mansuy
D
D
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008239:Lysine / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014633:Valine / Q000494:pharmacology
D009569:Nitric Oxide; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D001119:Arginase; D014633:Valine; D008239:Lysine