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J. Biol. Chem., Vol. 280, Issue 44, 36912-36919, November 4, 2005

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GTP Cyclohydrolase II Structure and Mechanism^*

Jingshan Ren1, Masayo Kotaka1, Michael Lockyer, Heather K. Lamb¶, Alastair R. Hawkins¶, and David K. Stammers2

From the Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, Biology Section, Arrow Therapeutics Ltd., Trinity Street, Borough, London, SE1 1DA, and ^¶Institute of Cell and Molecular Biosciences, Catherine Cookson Building, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom

GTP cyclohydrolase II converts GTP to 2,5-diamino-6--ribosyl-4(3H)-pyrimidinone 5'-phosphate, formate and pyrophosphate, the first step in riboflavin biosynthesis. The essential role of riboflavin in metabolism and the absence of GTP cyclohydrolase II in higher eukaryotes makes it a potential novel selective antimicrobial drug target. GTP cyclohydrolase II catalyzes a distinctive overall reaction from GTP cyclohydrolase I; the latter converts GTP to dihydroneopterin triphosphate, utilized in folate and tetrahydrobiopterin biosynthesis. The structure of GTP cyclohydrolase II determined at 1.54-Å resolution reveals both a different protein fold to GTP cyclohydrolase I and distinctive molecular recognition determinants for GTP; although in both enzymes there is a bound catalytic zinc. The GTP cyclohydrolase II·GMPCPP complex structure shows Arg¹²⁸ interacting with the -phosphonate, and thus in the case of GTP, Arg¹²⁸ is positioned to act as the nucleophile for pyrophosphate release and formation of the proposed covalent guanylyl-GTP cyclohydrolase II intermediate. Tyr¹⁰⁵ is identified as playing a key role in GTP ring opening; it is hydrogen-bonded to the zinc-activated water molecule, the latter being positioned for nucleophilic attack on the guanine C-8 atom. Although GTP cyclohydrolase I and GTP cyclohydrolase II both use a zinc ion for the GTP ring opening and formate release, different residues are utilized in each case to catalyze this reaction step.

Received for publication, July 15, 2005 , and in revised form, August 10, 2005.

The atomic coordinates and structure factors (code 2BZ1, 2BZ0) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Arrow Therapeutics and the UK Biotechnology and Biological Sciences Research Council. 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 44-1865-287-565; Fax: 44-1865-287-547; E-mail: daves{at}strubi.ox.ac.uk.

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