Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity.
Guanosine triphosphate (GTP) cyclohydrolase I, the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), is subject to feedback inhibition by BH4, a cofactor for phenylalanine hydroxylase. Inhibition was found to depend specifically on BH4 and the presence of another protein (p35). The inhibition occurred through BH4-dependent complex formation between p35 protein and GTP cyclohydrolase I. Furthermore, the inhibition was specifically reversed by phenylalanine, and, in conjunction with p35, phenylalanine reduced the cooperativity of GTP cyclohydrolase I. These findings also provide a molecular basis for high plasma BH4 concentrations observed in patients with hyperphenylalaninemia caused by phenylalanine hydroxylase deficiency.
Department of Biochemistry, Osaka Medical College, Japan.
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Harada
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Kagamiyama
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Hatakeyama
D000818:Animals; D001685:Biological Factors / Q000502:physiology; D001708:Biopterins / Q000031:analogs & derivatives / Q000502:physiology; D002850:Chromatography, Gel; D005246:Feedback; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D010649:Phenylalanine / Q000502:physiology; D010651:Phenylalanine Hydroxylase / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014020:Tissue Extracts
D001685:Biological Factors; D011994:Recombinant Proteins; D014020:Tissue Extracts; D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; D006136:GTP Cyclohydrolase; C003402:sapropterin