cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells.
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Shiraishi H, Kato T, Atsuta K, Sumi-Ichinose C, Ohtsuki M, Itoh M, Hishida H, Tada S, Udagawa Y, Nagatsu T, Hagino Y, Ichinose H, Nomura T
cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells.
J Pharmacol Sci. 2003 Nov;93(3):265-71.
- PubMed ID
- 14646243 [ View in PubMed]
- Abstract
Tetrahydrobiopterin (BH4) acts as an essential cofactor for the enzymatic activity of nitric oxide (NO) synthases. Biosynthesis of the cofactor BH4 starts from GTP and requires 3 enzymatic steps, which include GTP cyclohydrolase I (GCH I) catalysis of the first and rate-limiting step. In this study we examined the effects of cGMP on GCH I activity in human umbilical vein endothelial cells under inflammatory conditions. Exogenous application of the cGMP analogue 8-bromo-cGMP markedly inhibited GCH I activity in the short term, whereas an cAMP analogue had no effect on GCH I activity under the same condition. NO donors, NOR3 and sodium nitroprusside, elevated the intracellular cGMP level and reduced GCH I activity in the short term. This inhibition of GCH I activity was obliterated in the presence of an NO trapper carboxy-PTIO. NO donors had no effect on GCH I mRNA expression in the short term. Moreover, cycloheximide did not alter the inhibition by NO donors of GCH I activity. These findings suggest that stimulation of the cGMP signaling cascade down-regulates GCH I activity through post translational modification of the GCH I enzyme.