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J Biol Chem, Vol. 274, Issue 35, 24921-24929, August 27, 1999

Tetrahydrobiopterin Inhibits Monomerization and Is Consumed during Catalysis in Neuronal NO Synthase

Andreas Reif, Lothar G. Fröhlich, Peter Kotsonis, Armin Frey, Heike M. Bömmel, David A. Wink**, Wolfgang PfleidererDagger Dagger , and Harald H. H. W. Schmidt

From the Department of Pharmacology and Toxicology, Julius-Maximilians-University, Würzburg, 97078 Germany, the ** National Cancer Institute, Bethesda, Maryland 20892, and the Dagger Dagger  Faculty of Chemistry, University of Konstanz, Konstanz, 78434 Germany

The biosynthesis of nitric oxide (NO) is catalyzed by homodimeric NO synthases (NOS). For unknown reasons, all NOS co-purify with substoichiometric amounts of (6R)-5,6,7,8-tetrahydrobiopterin (H4Bip) and require additional H4Bip for maximal activity. We examined the effects of H4Bip and pterin-derived inhibitors (anti-pterins) on purified neuronal NOS-I quaternary structure and H4Bip content. During L-arginine turnover, NOS-I dimers time dependently dissociated into inactive monomers, paralleled by a loss of enzyme-associated pterin. Dimer dissociation was inhibited when saturating levels of H4Bip were added during catalysis. Similar results were obtained with pterin-free NOS-I expressed in Escherichia coli. This stabilizing effect of H4Bip was mimicked by the anti-pterin 2-amino-4,6-dioxo-3,4,5,6,8,8a,9,10-octahydro-oxazolo[1,2f]-pteridine (PHS-32), which also displaced NOS-associated H4Bip in a competitive manner. Surprisingly, H4Bip not only dissociated from NOS during catalysis, but was only partially recovered in the solute (50.0 ± 16.5% of control at 20 min). NOS-associated H4Bip appeared to react with a NOS catalysis product to a derivative distinct from dihydrobiopterin or biopterin. Under identical conditions, reagent H4Bip was chemically stable and fully recovered (95.5 ± 3.4% of control). A similar loss of both reagent and enzyme-bound H4Bip and dimer content was observed by NO generated from spermine NONOate. In conclusion, we propose a role for H4Bip as a dimer-stabilizing factor of neuronal NOS during catalysis, possibly by interfering with enzyme destabilizing products.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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