Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase
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The binding of tetrahydropteridines with 6-di- and trihydroxypropyl side chains to recombinant rat neuronal nitric oxide (NO) synthase (EC 1.14.13.39) was determined by competition with 6R-[3´-3H]-5,6,7,8-tetrahydro-L-erythro-biopterin (6R-[3´-3H]H4biopterin). Although all but one of the derivatives exhibited only poor affinities (Ki 50 µM), the 4-amino analogue of 6R-H4biopterin was a potent antagonist of 6R-H4biopterin binding (Ki 13.2 nM). The 4-amino analogue of 6R-H4 biopterin inhibited NO synthase stimulation by the natural cofactor 6R-H4biopterin with an IC50 of 1 µM without affecting the basal activity observed in the absence of added 6R-H4biopterin. Because the 4-amino analogue of 6R-H4biopterin also inhibited dihydropteridine reductase (EC 1.6.99.7; IC50 20 µM), our results support the hypothesis that redox cycling of H4biopterin might be required for the NO synthase reaction.
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- Authors
- WERNER, E. R., PITTERS, E., SCHMIDT, K., WACHTER, H., WERNER-FELMAYER, G., & MAYER, B.
- Affiliations
- Innsbruck Medical University (AT)
- University of Graz (AT)
- Institut für Medizinische Chemie und Biochemie der Unversität Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 1996-11-15
- Volume
- 320
- Issue
- 1
- Pages
- 193-196
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1217916
- OpenAlex
- W2183834813
- Cited by
- 86
- References
- 17
- Citations by year
- 2024: 1 · 2022: 1 · 2019: 2 · 2018: 1 · 2016: 1 · 2014: 6 · 2013: 3
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Oesterreichische Nationalbank
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- tetrahydrobiopterin, dihydropteridine reductase, neuronal nitric oxide synthase, redox cycling, cofactor binding, nitric oxide synthase inhibition, tetrahydropteridines
- MeSH terms
- Animals, Biopterins, Brain, Dihydropteridine Reductase, Kinetics, Neurons, Recombinant Proteins, Sheep, Spodoptera, Nitric Oxide Synthase, Rats
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