TY - JOUR
T1 - Oxidation of tetrahydrobiopterin by peroxynitrite
T2 - Implications for vascular endothelial function
AU - Milstien, Sheldon
AU - Katusic, Zvonimir
N1 - Funding Information:
Z.K. was supported in part by grants from the National Heart, Lung, and Blood Institute (HL-53542) and the Mayo Foundation.
PY - 1999/10/5
Y1 - 1999/10/5
N2 - Subsaturating levels of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase (NOS), can lead to endothelial dysfunction as a result of decreased production of nitric oxide. Furthermore, insufficient BH4 can also result in NOS-uncoupled production of reactive oxygen intermediates, such as superoxide anion and hydrogen peroxide. Nitric oxide and superoxide react rapidly to form peroxynitrite, which may be the reactive species responsible for many of the toxic effects of nitric oxide. Here we show that BH4 is a primary target for peroxynitrite-catalyzed oxidation because at pH 7.4, physioloscally relevant concentrations of BH4 are oxidized rapidly by low concentrations of peroxynitrite. Peroxynitrite oxidizes BH4 to quinonoid 5,6-dihydrobiopterin and a large proportion of the quinonoid isomer readily loses its side chain to form 7,8 dihydropterin which is not a cofactor for nitric oxide synthase. Thus, abnormally low levels of BH4 can promote a cycle of its own destruction mediated by nitric oxide synthase-dependent formation of peroxynitrite. This mechanism might contribute to vascular endothelial dysfunction induced by oxidative stress.
AB - Subsaturating levels of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase (NOS), can lead to endothelial dysfunction as a result of decreased production of nitric oxide. Furthermore, insufficient BH4 can also result in NOS-uncoupled production of reactive oxygen intermediates, such as superoxide anion and hydrogen peroxide. Nitric oxide and superoxide react rapidly to form peroxynitrite, which may be the reactive species responsible for many of the toxic effects of nitric oxide. Here we show that BH4 is a primary target for peroxynitrite-catalyzed oxidation because at pH 7.4, physioloscally relevant concentrations of BH4 are oxidized rapidly by low concentrations of peroxynitrite. Peroxynitrite oxidizes BH4 to quinonoid 5,6-dihydrobiopterin and a large proportion of the quinonoid isomer readily loses its side chain to form 7,8 dihydropterin which is not a cofactor for nitric oxide synthase. Thus, abnormally low levels of BH4 can promote a cycle of its own destruction mediated by nitric oxide synthase-dependent formation of peroxynitrite. This mechanism might contribute to vascular endothelial dysfunction induced by oxidative stress.
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U2 - 10.1006/bbrc.1999.1422
DO - 10.1006/bbrc.1999.1422
M3 - Article
C2 - 10512739
AN - SCOPUS:0033527413
SN - 0006-291X
VL - 263
SP - 681
EP - 684
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -