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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November 1996
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Research Article|
November 15 1996
Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase Available to Purchase
Ernst R. WERNER;
Ernst R. WERNER
‡
*Institut für Medizinische Chemie und Biochemie der Unversität Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
‡To whom correspondence should be addressed.
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Eva PITTERS;
Eva PITTERS
†Institut für Pharmakologie und Toxikologie der Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria
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Kurt SCHMIDT;
Kurt SCHMIDT
†Institut für Pharmakologie und Toxikologie der Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria
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Helmut WACHTER;
Helmut WACHTER
*Institut für Medizinische Chemie und Biochemie der Unversität Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Gabriele WERNER-FELMAYER;
Gabriele WERNER-FELMAYER
*Institut für Medizinische Chemie und Biochemie der Unversität Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria
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Bernd MAYER
Bernd MAYER
†Institut für Pharmakologie und Toxikologie der Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria
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Publisher: Portland Press Ltd
Received:
June 28 1996
Revision Received:
August 02 1996
Accepted:
August 05 1996
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 320 (1): 193–196.
Article history
Received:
June 28 1996
Revision Received:
August 02 1996
Accepted:
August 05 1996
Citation
Ernst R. WERNER, Eva PITTERS, Kurt SCHMIDT, Helmut WACHTER, Gabriele WERNER-FELMAYER, Bernd MAYER; Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase. Biochem J 15 November 1996; 320 (1): 193–196. doi: https://doi.org/10.1042/bj3200193
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