TETRAHYDROBIOPTERIN AND CYTOKINES

Biosynthesis of tetrahydrobiopterin starts from guanosine triphosphate by the action of guanosine triphosphate cyclohydrolase I, which yield s the first intermediate, 7,8-dihydroneopterin triphosphate. This comp ound is then converted by subsequent enzymes, 6-pyruvoyl tetrahydropte rin synthase and sepiapterin reductase, to tetrahydrobiopterin, the bi ologically active metabolite. Cytokines such as gamma-interferon or tu mor necrosis factor-alpha strongly stimulate the activity of guanosine triphosphate cyclohydrolase I in murine and human cells, yielding a p otentiation of intracellular tetrahydrobiopterin concentrations. In hu man cells, particularly in human monocytes and macrophages, the low ac tivity of 6-pyruvoyl tetrahydropterin synthase leads to the additional accumulation of neopterin derivatives, which leak from the cells afte r dephosphorylation and are found increased in body fluids of humans w ith diseases challenging cell-mediated immunity. A functional role for the stimulation of tetrahydrobiopterin biosynthesis by cytokines is t he formation of a limiting cofactor required for the enzymatic convers ion of L-arginine to citrulline and nitric oxide.