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J Biol Chem, Vol. 274, Issue 38, 26736-26742, September 17, 1999
From the The binding of calcium/calmodulin stimulates
electron transfer between the reductase and oxygenase domains of
neuronal nitric oxide synthase (nNOS). Here, we demonstrate using
electron spin resonance spin-trapping with
5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide that
pterin-free nNOS generates superoxide from the reductase and the
oxygenase domain by a calcium/calmodulin-dependent
mechanism. Tetrahydrobiopterin (BH4) diminishes the
formation of superoxide by a mechanism that does not cause inhibition
of NADPH consumption. In contrast, BH4 analogs
7,8-dihydrobiopterin and sepiapterin do not affect superoxide yields.
L-Arginine alone inhibits the generation of superoxide by
nNOS but not by C331A-nNOS mutant that has a low affinity for
L-arginine. A greater decrease in superoxide yields is
observed when nNOS is preincubated with L-arginine. This
effect is in accordance with the slow binding rates of
L-arginine to NOS in the absence of BH4.
L-Arginine alone or in combination with BH4
decreases the rates of NADPH consumption. The effect of
L-arginine on superoxide yields, however, was less dramatic than that caused by BH4 as much higher concentrations of
L-arginine are necessary to attain the same inhibition. In
combination, L-arginine and BH4 inhibit the
formation of superoxide generation and stimulate the formation of
L-citrulline. We conclude that, in contrast to L-arginine, BH4 does not inhibit the generation
of superoxide by controlling electron transfer through the enzyme but
by stimulating the formation of the heme-peroxo species.
Tetrahydrobiopterin-dependent Inhibition of
Superoxide Generation from Neuronal Nitric Oxide Synthase
§,
, Department of Pathology, Laboratoire
Structure et Réactivité des Espèces Paramagnetiques,
CNRS URA 1412, Université de Provence, 13397, Marseilles Cedex 20, France, and the ¶ Biochemistry
Department, University of Texas Health Science Center,
San Antonio, Texas 78284-7760
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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