title: cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiraishi
authors.forename: Taiya
authors.initials: T
authors.lastname: Kato
authors.forename: Koji
authors.initials: K
authors.lastname: Atsuta
authors.forename: Chiho
authors.initials: C
authors.lastname: Sumi-Ichinose
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Itoh
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hishida
authors.forename: Shin
authors.initials: S
authors.lastname: Tada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Udagawa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nagatsu
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hagino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Takahide
authors.initials: T
authors.lastname: Nomura
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D001708:Biopterins; D006136:GTP Cyclohydrolase; C003402:sapropterin; D006152:Cyclic GMP