PTPS is phosphorylated by cGMP-dependant protein kinase II GCH1 reduces GTP to dihydroneopterin triphosphate DHNTP is dephosphorylated by PTPS to PTHP PTHP is reduced to BH4 by sepiapterin reductase (SPR) Sepiapterin reductase (SPR) is phosphorylated by Ca2+/calmodulin-dependent protein kinase II Peroxynitrite can oxidise BH4 to the BH3 radical BH4 is oxidised to the BH3 radical during the eNOS catalytic cycle Ferrous iron reduces the BH3 radical back to BH4 Ascorbate can reduce the BH3 radical back to BH4 The BH3 radical can decay to dihydrobiopterin (BH2) BH2 binding can lead to eNOS uncoupling GCHFR binds to GCH1 and negatively regulates its activity Salvage - BH2 is reduced to BH4 by DHFR Salvage - Sepiapterin is reduced to BH2 PathwayStep2130 PathwayStep2133 PathwayStep2134 PathwayStep2131 PathwayStep2132 PathwayStep2129 PathwayStep2140 PathwayStep2141 PathwayStep2142 PathwayStep2136 PathwayStep2135 PathwayStep2138 PathwayStep2137 PathwayStep2139 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation Authored: Jassal, B, 2011-08-17 Edited: Jassal, B, 2011-08-17 Pubmed10727395 Pubmed17555404 Pubmed18321209 Pubmed21550412 Reactome Database ID Release 431474151 Reactome, http://www.reactome.org ReactomeREACT_111176 Reviewed: D'Eustachio, P, 2011-08-23 Tetrahydrobiopterin (BH4) is an essential co-factor for the aromatic amino acid hydroxylases and glycerol ether monooxygenase and it regulates nitric oxide synthase (NOS) activity. Inherited BH4 deficiency leads to hyperphenylalaninemia, and dopamine and neurotransmitter deficiency in the brain. BH4 maintains enzymatic coupling to L-arginine oxidation to produce NO. Oxidation of BH4 to BH2 results in NOS uncoupling, resulting in superoxide (O2.-) formation rather than NO. Superoxide rapidly reacts with NO to produce peroxynitrite which can further uncouple NOS.<br>These reactive oxygen species (superoxide and peroxynitrite) can contribute to increased oxidative stress in the endothelium leading to atherosclerosis and hypertension (Thöny et al. 2000, Crabtree & Channon 2011, Schulz et al. 2008, Schmidt & Alp 2007). The synthesis, recycling and effects of BH4 are shown here. Three enzymes are required for the de novo biosynthesis of BH4 and two enzymes for the recycling of BH4.