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J. Biol. Chem., Vol. 266, Issue 10, 6259-6263, Apr, 1991
DJ Stuehr, NS Kwon, CF Nathan, OW Griffith, PL Feldman and J Wiseman
Authentic N omega-hydroxy-L-arginine was synthesized and used to determine
whether it is an intermediate in nitric oxide (.NO) synthesis from
L-arginine by macrophage .NO synthase. The apparent Km (6.6 microM) and
Vmax (99 nmol x min-1 x mg-1) observed with N omega-hydroxy- L-arginine
were similar to those observed with L-arginine (Km = 2.3 microM; Vmax = 54
mumol x min-1 x mg-1). N omega-Hydroxy-D-arginine was not a substrate.
Stable isotope studies showed that .NO synthase exclusively oxidized the
hydroxylated nitrogen of N omega-hydroxy-L- arginine, forming .NO and
L-citrulline. As with L-arginine, O2 was the source of the ureido oxygen in
L-citrulline from N omega-hydroxy-L- arginine. In the presence of excess N
omega-hydroxy-L-arginine, .NO synthase generated a metabolite of
L-[14C]arginine that cochromatographed with authentic N
omega-hydroxy-L-arginine. The labeled metabolite exhibited identical
chromatographic behavior in three solvent systems and generated the same
product (L-citrulline) upon alkaline hydrolysis as authentic N
omega-hydroxy-L-arginine. Experiments were then run to identify which redox
cofactor (NADPH or tetrahydrobiopterin) participated in the enzymatic
synthesis of N omega- hydroxy-L-arginine. Both cofactors were required for
synthesis of .NO from either N omega-hydroxy-L-arginine or L-arginine.
However, with L- arginine, the synthesis of 1 mol of .NO was coupled to the
oxidation of 1.52 +/- 0.02 mol of NADPH; whereas with N
omega-hydroxy-L-arginine, only 0.53 +/- 0.04 mol of NADPH was oxidized per
mol of .NO formed. These results support a mechanism in which N
omega-hydroxy-L-arginine is generated as an intermediate in .NO synthesis
through an NADPH- dependent hydroxylation of L-arginine.
N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine
Department of Medicine, Cornell University Medical College, New York, New York 10021.
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Q. A. Albakri and D. J. Stuehr Intracellular Assembly of Inducible NO Synthase Is Limited by Nitric Oxide-mediated Changes in Heme Insertion and Availability J. Biol. Chem., March 8, 1996; 271(10): 5414 - 5421. [Abstract] [Full Text] [PDF]
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J. C. Salerno, C. Frey, K. McMillan, R. F. Williams, B. S. S. Masters, and O. W. Griffith Characterization by Electron Paramagnetic Resonance of the Interactions of L-Arginine and L-Thiocitrulline with the Heme Cofactor Region of Nitric Oxide Synthase J. Biol. Chem., November 17, 1995; 270(46): 27423 - 27428. [Abstract] [Full Text] [PDF]
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M. Sono, D. J. Stuehr, M. Ikeda-Saito, and J. H. Dawson Identification of Nitric Oxide Synthase as a Thiolate-ligated Heme Protein Using Magnetic Circular Dichroism Spectroscopy J. Biol. Chem., August 25, 1995; 270(34): 19943 - 19948. [Abstract] [Full Text] [PDF]
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K. L. Campos, J. Giovanelli, and S. Kaufman Characteristics of the Nitric Oxide Synthase-catalyzed Conversion of Arginine to N-Hydroxyarginine, the First Oxygenation Step in the Enzymic Synthesis of Nitric Oxide J. Biol. Chem., January 27, 1995; 270(4): 1721 - 1728. [Abstract] [Full Text] [PDF]
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A. Huang, J. A. Vita, R. C. Venema, and J. F. Keaney Jr. Ascorbic Acid Enhances Endothelial Nitric-oxide Synthase Activity by Increasing Intracellular Tetrahydrobiopterin J. Biol. Chem., June 2, 2000; 275(23): 17399 - 17406. [Abstract] [Full Text] [PDF]
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J. Santolini, S. Adak, C. M. L. Curran, and D. J. Stuehr A Kinetic Simulation Model That Describes Catalysis and Regulation in Nitric-oxide Synthase J. Biol. Chem., January 5, 2001; 276(2): 1233 - 1243. [Abstract] [Full Text] [PDF]
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K. M. Rusche and M. A. Marletta Reconstitution of Pterin-free Inducible Nitric-oxide Synthase J. Biol. Chem., January 5, 2001; 276(1): 421 - 427. [Abstract] [Full Text] [PDF]
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C.-C. Wei, Z.-Q. Wang, Q. Wang, A. L. Meade, C. Hemann, R. Hille, and D. J. Stuehr Rapid Kinetic Studies Link Tetrahydrobiopterin Radical Formation to Heme-dioxy Reduction and Arginine Hydroxylation in Inducible Nitric-oxide Synthase J. Biol. Chem., January 5, 2001; 276(1): 315 - 319. [Abstract] [Full Text] [PDF]
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J. Santolini, A. L. Meade, and D. J. Stuehr Differences in Three Kinetic Parameters Underpin the Unique Catalytic Profiles of Nitric-oxide Synthases I, II, and III J. Biol. Chem., December 21, 2001; 276(52): 48887 - 48898. [Abstract] [Full Text] [PDF]
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D. Stuehr, S. Pou, and G. M. Rosen Oxygen Reduction by Nitric-oxide Synthases J. Biol. Chem., April 27, 2001; 276(18): 14533 - 14536. [Full Text] [PDF]
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