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Final Report, FWF Project 13793 Biochemsitry of novel tetrahydrobiopterin derivatives,
Ernst R. Werner, Division of Biological Chemistry, Biocenter,Medical University of Innsbruck
Tetrahydrobiopterin is a compound with structural similarity to the vitamins folic acid and riboflavin. In contrast to these, tetrahydrobiopterin is synthesized by mammals. Tetrahydrobiopterin is required as cofactor for the metabolism of aromatic amino acids and for nitric oxide synthases. Nitric oxide synthases are a recently discovered family of proteins catalyzing the formation of nitric oxide from L-arginine. Nitric oxide regulates important physiological functions such as host defense to pathogens, blood pressure and neurotransmission.
This project succeeded in getting new insights into the mechanism of stimulation of nitric oxide synthases by tetrahydrobiopterin by the use of novel tetrahydrobiopterin derivatives as unique tools. We could show that tetrahydrobiopterin stimulates nitric oxide synthases by a novel mechanism that involves the formation of a radical derived from tetrahydrobiopterin. This novel mechanism proved to be clearly different from the mechansim of stimulation of phenylalanine hydroxylase by tetrahydrobiopterin.We could also demonstrate that one of the derivatives used, the 4-amino analogue of tetrahydrobiopterin, is a compound with promising pharmacological action. This compound is able to counteract the deadly side effects of septic shock and is an immunosuppressant, which efficiently blocks the rejection of allografts.
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