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Lookup NU author(s): Dr Heather Lamb,
Professor Alastair Hawkins
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GTP cyclohydrolase II converts GTP to 2,5-diamino-6-β-ribosyl-4(3N)- 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 α-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. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
Author(s): Ren J, Kotaka M, Lockyer M, Lamb HK, Hawkins AR, Stammers DK
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology, Inc.
PubMed id: 16115872
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