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J. Biol. Chem., Vol. 281, Issue 44, 33302-33312, November 3, 2006

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A typical N-terminal Extensions Confer Novel Regulatory Properties on GTP Cyclohydrolase Isoforms in Drosophila melanogaster^*

From the Department of Biological Sciences, University of Alabama, Tuscaloosa, Alabama 35487

The cofactor tetrahydrobiopterin plays critical roles in the modulation of the signaling molecules dopamine, serotonin, and nitric oxide. Deficits in cofactor synthesis have been associated with several human hereditary diseases. Responsibility for the regulation of cofactor pools resides with the first enzyme in its biosynthetic pathway, GTP cyclohydrolase I. Because organisms must be able to rapidly respond to environmental and developmental cues to adjust output of these signaling molecules, complex regulatory mechanisms are vital for signal modulation. Mammalian GTP cyclohydrolase is subject to end-product inhibition via an associated regulatory protein and to positive regulation via phosphorylation, although target residues are unknown. GTP cyclohydrolase is composed of a highly conserved homodecameric catalytic core and non-conserved N-terminal domains proposed to be regulatory sites. We demonstrate for the first time in any organism that the N-terminal arms of the protein serve regulatory functions. We identify two different modes of regulation of the enzyme mediated through the N-terminal domains. The first is end-product feedback inhibition, catalytically similar to that of the mammalian enzyme, except that feedback inhibition by the cofactor requires sequences in the N-terminal arms rather than a separate regulatory protein. The second is a novel inhibitory interaction between the N-terminal arms and the active sites, which can be alleviated through the phosphorylation of serine residues within the N termini. Both mechanisms allow for acute and highly responsive regulation of cofactor production as required by downstream signaling pathways.

Received for publication, March 8, 2006 , and in revised form, August 2, 2006.

We dedicate this paper to the memory of the late Edward Weisberg, whose pioneering doctoral research in Drosophila GTPCH biochemical analysis set the stage for the work reported here.

^* This work was supported by National Institutes of Health Grant GM62879 (to J. M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4 and Table S1.

¹ Both authors contributed equally to this work.

² Present address: Center for Behavioral Neuroscience, Emory University School of Medicine, Atlanta, GA 30329.

³ Present address: Dept. of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599.

⁴ Present address: Dept. of Orthopedic Surgery, School of Medicine, Stanford University, 300 Pasteur Drive, Palo Alto, CA 94305.

⁵ To whom correspondence should be addressed: Dept. of Biological Sciences, University of Alabama, Box 870344, 411 Hackberry Lane, Tuscaloosa, AL 35487-0344. Tel.: 205-348-7738; Fax: 205-348-1786; E-mail: jodonnel{at}bama.ua.edu.

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