Oxidation of tetrahydrobiopterin by peroxynitrite: Implications for vascular endothelial function

Subsaturating levels of tetrahydrobiopterin (BH4), an essential cofactor fo r nitric oxide synthase (NOS), can lead to endothelial dysfunction as a res ult of decreased production of nitric oxide. Furthermore, insufficient BH4 can also result in NOS-uncoupled production of reactive oxygen intermediate s, such as superoxide anion and hydrogen peroxide. Nitric oxide and superox ide react rapidly to form peroxynitrite, which may be the reactive species responsible for many of the toxic effects of nitric oxide, Here we show tha t BH4 is a primary target for peroxynitrite-catalyzed oxidation because at pH 7.4, physiologically relevant concentrations of HH, are oxidized rapidly by low concentrations of peroxynitrite. Peroxynitrite oxidizes BH4 to quin onoid 5,6-dihydrobiopterin and a large proportion of the quinonoid isomer r eadily loses its side chain to form 7,8-dihydropterin which is not a cofact or for nitric oxide synthase, Thus, abnormally low levels of BH4 can promot e a cycle of its own destruction mediated by nitric oxide synthase-dependen t formation of peroxynitrite, This mechanism might contribute to vascular e ndothelial dysfunction induced by oxidative stress, (C) 1999 Academic Press .