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          Institute: MPI für Biochemie     Collection: Structure Research (R. Huber)     Display Documents



  history
ID: 41682.0, MPI für Biochemie / Structure Research (R. Huber)
Biosynthesis of pteridines. Reaction mechanism of GTP cyclohydrolase I
Authors:Rebelo, J.; Auerbach, G.; Bader, G.; Bracher, A.; Nar, H.; Hösl, C.; Schramek, N.; Kaiser, J.; Bacher, A.; Huber, R.; Fischer, M.
Language:English
Date of Publication (YYYY-MM-DD):2003-02-14
Title of Journal:Journal of Molecular Biology
Journal Abbrev.:J. Mol. Biol.
Volume:326
Issue / Number:2
Start Page:503
End Page:516
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:GTP cyclohydrolase I catalyses the hydrolytic release of formate from GTP followed by cyclization to dihydroneopterin triphosphate. The enzymes from bacteria and animals are homodecamers containing one zinc ion per subunit. Replacement of Cys110, Cys181, His112 or His113 of the enzyme from Escherichia coli by serine affords catalytically inactive mutant proteins with reduced capacity to bind zinc. These mutant proteins are unable to convert GTP or the committed reaction intermediate, 2-amino-5-formylamino-6-(beta- ribosylamino)-4(3H)-pyrimidinone 5'-triphosphate, to dihydroneopterin triphosphate. The crystal structures of GTP complexes of the His113Ser, His112Ser and Cys181Ser mutant proteins determined at resolutions of 2.5 Angstrom, 2.8 Angstrom and 3.2 Angstrom, respectively, revealed the conformation of substrate GTP in the active site cavity. The carboxylic group of the highly conserved residue Glu152 anchors the substrate GTP, by hydrogen bonding to N-3 and to the position 2 amino group. Several basic amino acid residues interact with the triphosphate moiety of the substrate. The structure of the His112Ser mutant in complex with an undefined mixture of nucleotides determined at a resolution of 2.1 Angstrom afforded additional details of the peptide folding. Comparison between the wild-type and mutant enzyme structures indicates that the catalytically active zinc ion is directly coordinated to Cys110, Cys181. and His113. Moreover, the zinc ion is complexed to a water molecule, which is in close hydrogen bond contact to His112. In close analogy to zinc proteases, the zinc-coordinated water molecule is suggested to attack C-8 of the substrate affording a zinc-bound 8R hydrate of GTP. Opening of the hydrated imidazole ring affords a formamide derivative, which remains coordinated to zinc. The subsequent hydrolysis of the formamide motif has an absolute requirement for zinc ion catalysis. The hydrolysis of the formamide bond shows close mechanistic similarity with peptide hydrolysis by zinc proteases. (C) 2003 Elsevier Science Ltd. All rights reserved.
Free Keywords:biosynthesis; folic acid; crystal structure; GTP cyclohydrolase I; tetrahydrobiopterin
Comment of the Author/Creator:Date: 2003, FEB 14
External Publication Status:published
Document Type:Article
Communicated by:N.N.
Affiliations:MPI für Biochemie/Structure Research (Huber)
MPI für Biochemie/Cellular Biochemistry (F.-U. Hartl)/Research Group A. Bracher
External Affiliations:Tech Univ Munich, Lehrstuhl Organ Chem & Biochem,; Lichtenbergstr 4, D-85747 Garching, Germany; Tech Univ Munich, Lehrstuhl Organ Chem & Biochem, D-85747 Garching, Germany; Univ Nova Lisboa, Dept Quim, FCT, REQUIMTE,CQFB, P-2829516 Caparica, Portugal
Identifiers:ISI:000181068900014 [ID No:1]
ISSN:0022-2836 [ID No:2]
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