title: Metabolism of tetrahydrobiopterin: its relevance in monoaminergic neurons and neurological disorders.
abstract: (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for aromatic amino acid hydroxylases, such as phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), tryptophan hydroxylase, and nitric oxide synthase, which catalyze physiologically important reactions in mammals. The biosynthesis and metabolism of BH4 is usually studied mostly in the liver and only slightly in the brain, as the BH4 level in the liver is relatively high because BH4 is required for the reaction of PAH. We found that GTP (guanosine triphosphate) cyclohydrolase I, an enzyme for the biosynthesis of BH4, is a causative gene for DOPA (3,4-dihydroxyphenylalanine)-responsive dystonia (also called Segawa's disease), and that partial deficiency of BH4 leads to the dysfunction of the nigrostriatal dopaminergic neurons without hyperphenylalaninemia. We analyzed BH4-deficient mice that were produced by disruption of a BH4-synthesizing gene by a gene-knockout technique. We found that the protein amount of TH was highly dependent on the amount of BH4, especially in nerve terminals. Our research suggests that BH4 metabolism in the brain should be different from that in the liver, and that altered metabolism of BH4 should lead to neuropsychiatric disorders including Parkinson's disease.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan. hichinos@bio.titech.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Takahide
authors.initials: T
authors.lastname: Nomura
authors.forename: Chiho
authors.initials: C
authors.lastname: Sumi-Ichinose
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D020821:Dystonic Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D015306:Biogenic Monoamines; D001708:Biopterins; D006899:Mixed Function Oxygenases; D006136:GTP Cyclohydrolase; C003402:sapropterin