GTP cyclohydrolase II structure and mechanism.

Journal article

GTP cyclohydrolase II converts GTP to 2,5-diamino-6-beta-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-A 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 Arg(128) interacting with the alpha-phosphonate, and thus in the case of GTP, Arg(128) is positioned to act as the nucleophile for pyrophosphate release and formation of the proposed covalent guanylyl-GTP cyclohydrolase II intermediate. Tyr(105) 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.

Authors: Ren, J; Kotaka, M; Lockyer, M; Lamb, H; Hawkins, A

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 280
• Issue: 44
• Pages: 36912-36919
• Publication date: 2005-11-01
• DOI: 10.1074/jbc.m507725200
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Crystallography, X-Ray; Zinc; Tyrosine; Guanosine Triphosphate; Binding Sites; Molecular Structure; GTP Cyclohydrolase; Crystallization; Escherichia coli; Protein Conformation