TAILIEUCHUNG - Báo cáo khóa học: GTP cyclohydrolase I utilizes metal-free GTP as its substrate

GTP cyclohydrolase I (GCH) is the rate-limiting enzyme for the synthesis of tetrahydrobiopterin and its activity is important in the regulation of monoamine neurotransmit-ters such as dopamine, norepinephrine and serotonin. We have studied the action of divalent cations on the enzyme activity of purified recombinant human GCH expressed in Escherichia coli. First, we showed that the enzyme activity is dependent on the concentration ofMg-freeGTP. Inhibition of the enzyme activity by Mg 2+ ,aswellasbyMn 2+ ,Co 2+ or Zn 2+ , was due to the reduction of the availability of metal-free GTP substrate for the enzyme, when a divalent cation was present at a relatively high concentration with respect toGTP | Eur. J. Biochem. 271 349-355 2004 FEBS 2003 doi GTP cyclohydrolase I utilizes metal-free GTP as its substrate Takahiro Suzuki1 2 Hideki Kurita3 and Hiroshi Ichinose1 2 1 Department of Life Science Graduate School of Bioscience and Biotechnology Tokyo Institute of Technology Yokohama Japan 1 Division of Molecular Genetics Institute for Comprehensive Medical Science 3Department of Hygiene School of Medicine Fujita Health University Aichi Japan GTP cyclohydrolase I GCH is the rate-limiting enzyme for the synthesis of tetrahydrobiopterin and its activity is important in the regulation of monoamine neurotransmitters such as dopamine norepinephrine and serotonin. We have studied the action of divalent cations on the enzyme activity of purified recombinant human GCH expressed in Escherichia coli. First we showed that the enzyme activity is dependent on the concentration of Mg-free GTP. Inhibition of the enzyme activity by Mg2 as well as by Mn2 Co2 or Zn2 was due to the reduction of the availability of metal-free GTP substrate for the enzyme when a divalent cation was present at a relatively high concentration with respect to GTP. We next examined the requirement of Zn2 for enzyme activity by the use of a protein refolding assay because the recombinant enzyme contained approximately one zinc atom per subunit of the decameric protein. Only when Zn2 was present was the activity of the denatured enzyme effectively recovered by incubation with a chaperone protein. These are the first data demonstrating that GCH recognizes Mg-free GTP and requires Zn2 for its catalytic activity. We suggest that the cellular concentration of divalent cations can modulate GCH activity and thus tetrahydrobiopterin biosynthesis as well. Keywords GTP cyclohydrolase I magnesium recombinant protein tetrahydrobiopterin zinc. Metal ions are essential for many physiological functions of the brain. They may also induce or aggravate numerous neurodegenerative processes. .

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