4,4-Difluorinated analogues of l-arginine and N(G)-hydroxy-l-arginine as mechanistic probes for nitric oxide synthase.
4,4-Difluoro-l-arginine and 4,4-difluoro-N(G)-hydroxy-l-arginine were synthesized and shown to be substrates for the inducible isoform of nitric oxide synthase (iNOS). Binding of both fluorinated analogues to the NOS active site was also investigated using a spectral binding assay employing a heme domain construct of the inducible NOS isoform (iNOS(heme)). 4,4-Difluoro-N(G)-hydroxy-arginine was found to bind at the NOS active site in a unique manner consistent with a model involving ligation of the Fe(III) heme center by the oxygen atom of the N(G)-hydroxy moiety.
Martin
Nathaniel I
NI
Department of Medicinal Chemistry and Chemical Biology, University of Utrecht, 3584 CA, The Netherlands.
Woodward
Joshua J
JJ
Winter
Michael B
MB
Marletta
Michael A
MA
D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry; D006418:Heme / Q000737:chemistry; D008956:Models, Chemical; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D020033:Protein Isoforms; D005461:Fluorine; D006418:Heme; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D010100:Oxygen