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Science 4 June 1993:
Vol. 260. no. 5113, pp. 1507 - 1510
DOI: 10.1126/science.8502995
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Articles

Science, Vol 260, Issue 5113, 1507-1510
Copyright © 1993 by American Association for the Advancement of Science

articles

Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity

T Harada, H Kagamiyama, and K Hatakeyama

Department of Biochemistry, Osaka Medical College, Japan.

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.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
GTP Cyclohydrolase I Expression, Protein, and Activity Determine Intracellular Tetrahydrobiopterin Levels, Independent of GTP Cyclohydrolase Feedback Regulatory Protein Expression.
A. L. Tatham, M. J. Crabtree, N. Warrick, S. Cai, N. J. Alp, and K. M. Channon (2009)
J. Biol. Chem. 284, 13660-13668
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Direct Binding of GTP Cyclohydrolase and Tyrosine Hydroxylase: REGULATORY INTERACTIONS BETWEEN KEY ENZYMES IN DOPAMINE BIOSYNTHESIS.
K. M. Bowling, Z. Huang, D. Xu, F. Ferdousy, C. D. Funderburk, N. Karnik, W. Neckameyer, and J. M. O'Donnell (2008)
J. Biol. Chem. 283, 31449-31459
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Deficient BH4 production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes.
I. A. Ionova, J. Vasquez-Vivar, J. Whitsett, A. Herrnreiter, M. Medhora, B. C. Cooley, and G. M. Pieper (2008)
Am J Physiol Heart Circ Physiol 295, H2178-H2187
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Oral Administration of Tetrahydrobiopterin Attenuates Testicular Damage by Reducing Nitric Oxide Synthase Activity in a Cryptorchid Mouse Model.
Y. Kondo, T. Ishikawa, K. Yamaguchi, T. Yada, and M. Fujisawa (2008)
J Androl 29, 153-163
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Over-expression of GTP-cyclohydrolase 1 feedback regulatory protein attenuates LPS and cytokine-stimulated nitric oxide production.
M. Nandi, P. Kelly, P. Vallance, and J. Leiper (2008)
Vascular Medicine 13, 29-36
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A typical N-terminal Extensions Confer Novel Regulatory Properties on GTP Cyclohydrolase Isoforms in Drosophila melanogaster.
C. D. Funderburk, K. M. Bowling, D. Xu, Z. Huang, and J. M. O'Donnell (2006)
J. Biol. Chem. 281, 33302-33312
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Novel Reaction Mechanism of GTP Cyclohydrolase I. High-Resolution X-Ray Crystallography of Thermus thermophilus HB8 Enzyme Complexed with a Transition State Analogue, the 8-Oxoguanine Derivative.
Y. Tanaka, N. Nakagawa, S. Kuramitsu, S. Yokoyama, and R. Masui (2005)
J. Biochem. 138, 263-275
   Abstract »    Full Text »    PDF »
Structural Basis of Biopterin-induced Inhibition of GTP Cyclohydrolase I by GFRP, Its Feedback Regulatory Protein.
N. Maita, K. Hatakeyama, K. Okada, and T. Hakoshima (2004)
J. Biol. Chem. 279, 51534-51540
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The Mechanism of Potent GTP Cyclohydrolase I Inhibition by 2,4-Diamino-6-hydroxypyrimidine: REQUIREMENT OF THE GTP CYCLOHYDROLASE I FEEDBACK REGULATORY PROTEIN.
M. A. Kolinsky and S. S. Gross (2004)
J. Biol. Chem. 279, 40677-40682
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Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease.
N. J. Alp and K. M. Channon (2004)
Arterioscler Thromb Vasc Biol 24, 413-420
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GTP Cyclohydrolase I: Purification, Characterization, and Effects of Inhibition on Nitric Oxide Synthase in Nocardia Species.
A. He and J. P. N. Rosazza (2003)
Appl. Envir. Microbiol. 69, 7507-7513
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Dwarfism and Low Insulin-like Growth Factor-1 Due to Dopamine Depletion in Pts-/- Mice Rescued by Feeding Neurotransmitter Precursors and H4-biopterin.
L. Elzaouk, W. Leimbacher, M. Turri, B. Ledermann, K. Burki, N. Blau, and B. Thony (2003)
J. Biol. Chem. 278, 28303-28311
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Nitric Oxide (NO) Pretreatment Increases Cytokine-induced NO Production in Cultured Rat Hepatocytes by Suppressing GTP Cyclohydrolase I Feedback Inhibitory Protein Level and Promoting Inducible NO Synthase Dimerization.
J.-H. Park, H.-J. Na, Y.-G. Kwon, K.-S. Ha, S.-J. Lee, C.-K. Kim, K.-S. Lee, T. Yoneyama, K. Hatakeyama, P. K. M. Kim, et al. (2002)
J. Biol. Chem. 277, 47073-47079
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Bacterial Lipopolysaccharide Down-regulates Expression of GTP Cyclohydrolase I Feedback Regulatory Protein.
E. R. Werner, S. Bahrami, R. Heller, and G. Werner-Felmayer (2002)
J. Biol. Chem. 277, 10129-10133
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Divergence in Regulation of Nitric-oxide Synthase and Its Cofactor Tetrahydrobiopterin by Tumor Necrosis Factor-alpha . CERAMIDE POTENTIATES NITRIC OXIDE SYNTHESIS WITHOUT AFFECTING GTP CYCLOHYDROLASE I ACTIVITY.
L. R. Vann, S. Twitty, S. Spiegel, and S. Milstien (2000)
J. Biol. Chem. 275, 13275-13281
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Anti-pterins as Tools to Characterize the Function of Tetrahydrobiopterin in NO Synthase.
H. M. Bommel, A. Reif, L. G. Frohlich, A. Frey, H. Hofmann, D. M. Marecak, V. Groehn, P. Kotsonis, M. La, S. Koster, et al. (1998)
J. Biol. Chem. 273, 33142-33149
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GTP Cyclohydrolase I Inhibition by the Prototypic Inhibitor 2,4-Diamino-6-Hydroxypyrimidine. MECHANISMS AND UNANTICIPATED ROLE OF GTP CYCLOHYDROLASE I FEEDBACK REGULATORY PROTEIN.
L. Xie, J. A. Smith, and S. S. Gross (1998)
J. Biol. Chem. 273, 21091-21098
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Decameric GTP Cyclohydrolase I Forms Complexes with Two Pentameric GTP Cyclohydrolase I Feedback Regulatory Proteins in the Presence of Phenylalanine or of a Combination of Tetrahydrobiopterin and GTP.
T. Yoneyama and K. Hatakeyama (1998)
J. Biol. Chem. 273, 20102-20108
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GTP Cyclohydrolase I Feedback Regulatory Protein Is a Pentamer of Identical Subunits. PURIFICATION, cDNA CLONING, AND BACTERIAL EXPRESSION.
T. Yoneyama, J. M. Brewer, and K. Hatakeyama (1997)
J. Biol. Chem. 272, 9690-9696
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Competition for Tetrahydrobiopterin between Phenylalanine Hydroxylase and Nitric Oxide Synthase in Rat Liver.
C. M. Pastor, D. Williams, T. Yoneyama, K. Hatakeyama, S. Singleton, E. Naylor, and T. R. Billiar (1996)
J. Biol. Chem. 271, 24534-24538
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Purification and Cloning of the GTP Cyclohydrolase I Feedback Regulatory Protein, GFRP.
S. Milstien, H. Jaffe, D. Kowlessur, and T. I. Bonner (1996)
J. Biol. Chem. 271, 19743-19751
   Abstract »    Full Text »    PDF »
Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin.
K. Schallreuter, J. Wood, M. Pittelkow, M Gutlich, K. Lemke, W Rodl, N. Swanson, K Hitzemann, and I Ziegler (1994)
Science 263, 1444-1446
   Abstract »    PDF »
Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP.
N. Maita, K. Okada, K. Hatakeyama, and T. Hakoshima (2002)
PNAS 99, 1212-1217
   Abstract »    Full Text »    PDF »


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