First non-alpha-amino acid guanidines acting as efficient NO precursors upon oxidation by NO-synthase II or activated mouse macrophages.
A study of the oxidation of a series of guanidines related to L-arginine (L-Arg) and of various alkyl- and arylguanidines, by recombinant NO-synthase II (NOS II), led us to the discovery of the first non-alpha-amino acid guanidine substrate of NOS, acting as an efficient NO precursor. This compound, 3-(trifluoromethyl)propylguanidine, 4, led to a rate of NO formation (k(cat) = 220 +/- 50 min(-1)) only 2 times lower than that of L-Arg. Formation of 1 mol of NO upon NOS II-catalyzed oxidation of 4 occurred with consumption of 2.9 mol of NADPH, which corresponds to a 52% coupling between electron transfer and oxygenation of its guanidine function. Its oxidation by activated mouse macrophages in an L-Arg-free medium resulted in NO(2)(-) formation that was inhibited by classical NOS inhibitors with a rate only 2-3 times lower than that observed with L-Arg itself. These results open the way toward the research of selective, stable guanidine substrates of NOS that could be interesting, new NO donors after in situ oxidation by a given NOS isoform.
UMR 8601 CNRS, Université Paris V R. Descartes, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Sylvie
S
Dijols
Jean-Luc
JL
Boucher
Michel
M
Lepoivre
David
D
Lefevre-Groboillot
Magali
M
Moreau
Yves
Y
Frapart
Eleni
E
Rekka
Abigail L
AL
Meade
Dennis J
DJ
Stuehr
Daniel
D
Mansuy
D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D006146:Guanidines / Q000378:metabolism*; D007700:Kinetics; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009249:NADP / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000378:metabolism
D006146:Guanidines; D011994:Recombinant Proteins; D009569:Nitric Oxide; D009249:NADP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II