PDBsum entry 1n3r

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Hydrolase PDB id
Jmol PyMol
Protein chains
(+ 9 more) 221 a.a. *
GTP ×15
Waters ×79
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Biosynthesis of pteridins. Reaction mechanism of gtp cyclohydrolase i
Structure: Gtp cyclohydrolase i. Chain: a, b, c, d, e, f, g, h, i, j, k, l, m, n, o. Engineered: yes. Mutation: yes
Source: Escherichia coli. Organism_taxid: 562. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Pentamer (from PQS)
2.80Å     R-factor:   0.218     R-free:   0.272
Authors: J.Rebelo,G.Auerbach,G.Bader,A.Bracher,H.Nar,C.Hoesl, N.Schramek,J.Kaiser,A.Bacher,R.Huber,M.Fischer
Key ref:
J.Rebelo et al. (2003). Biosynthesis of pteridines. Reaction mechanism of GTP cyclohydrolase I. J Mol Biol, 326, 503-516. PubMed id: 12559918 DOI: 10.1016/S0022-2836(02)01303-7
29-Oct-02     Release date:   14-Oct-03    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P0A6T5  (GCH1_ECOLI) -  GTP cyclohydrolase 1
222 a.a.
221 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Gtp cyclohydrolase i.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Folate Biosynthesis (early stages)
      Reaction: GTP + H2O = formate + 2-amino-4-hydroxy-6-(erythro-1,2,3- trihydroxypropyl)-dihydropteridine triphosphate
Bound ligand (Het Group name = GTP)
corresponds exactly
+ H(2)O
= formate
+ 2-amino-4-hydroxy-6-(erythro-1,2,3- trihydroxypropyl)-dihydropteridine triphosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     protein complex   3 terms 
  Biological process     metabolic process   5 terms 
  Biochemical function     catalytic activity     7 terms  


    Added reference    
DOI no: 10.1016/S0022-2836(02)01303-7 J Mol Biol 326:503-516 (2003)
PubMed id: 12559918  
Biosynthesis of pteridines. Reaction mechanism of GTP cyclohydrolase I.
J.Rebelo, G.Auerbach, G.Bader, A.Bracher, H.Nar, C.Hösl, N.Schramek, J.Kaiser, A.Bacher, R.Huber, M.Fischer.
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 2.5A, 2.8A and 3.2A, 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 2.1A 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.
  Selected figure(s)  
Figure 1.
Figure 1. Hypothetical mechanism of the reaction catalysed by GTP cyclohydrolase I.[8.]
Figure 4.
Figure 4. Stereo diagram from the active site of the E. coli GTP cyclohydrolase I His113Ser mutant in complex with the substrate GTP. The GTP molecule (shown as a transparent wire model representation) is embedded in a large hydrogen bond network (broken lines) within the active site. Amino acid residues are shown as ball-and-stick models coloured according to the subunit to which they belong: A, red; B, blue; and D, green. The Figure was created using MOLSCRIPT[39.] and Raster3D. [40.]
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 326, 503-516) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19767425 B.Sankaran, S.A.Bonnett, K.Shah, S.Gabriel, R.Reddy, P.Schimmel, D.A.Rodionov, Crécy-Lagard, J.D.Helmann, D.Iwata-Reuyl, and M.A.Swairjo (2009).
Zinc-independent folate biosynthesis: genetic, biochemical, and structural investigations reveal new metal dependence for GTP cyclohydrolase IB.
  J Bacteriol, 191, 6936-6949.
PDB codes: 3d1t 3d2o
19862738 S.E.Gibbons, I.Stayton, and Y.Ma (2009).
Optimization of urinary pteridine analysis conditions by CE-LIF for clinical use in early cancer detection.
  Electrophoresis, 30, 3591-3597.  
18721750 R.M.McCarty, and V.Bandarian (2008).
Deciphering deazapurine biosynthesis: pathway for pyrrolopyrimidine nucleosides toyocamycin and sangivamycin.
  Chem Biol, 15, 790-798.  
17518419 A.Tazumi, S.Saito, T.Sekizuka, O.Murayama, J.E.Moore, B.C.Millar, and M.Matsuda (2007).
Molecular characterization of the non-coding promoter and leader regions and full-length 16S ribosomal RNA (rRNA) gene of Taylorella asinigenitalis.
  J Basic Microbiol, 47, 260-265.  
17669425 B.Nocek, E.Evdokimova, M.Proudfoot, M.Kudritska, L.L.Grochowski, R.H.White, A.Savchenko, A.F.Yakunin, A.Edwards, and A.Joachimiak (2007).
Structure of an amide bond forming F(420):gamma-glutamyl ligase from Archaeoglobus fulgidus -- a member of a new family of non-ribosomal peptide synthases.
  J Mol Biol, 372, 456-469.
PDB codes: 2g9i 2phn
17255002 W.Martin, and M.J.Russell (2007).
On the origin of biochemistry at an alkaline hydrothermal vent.
  Philos Trans R Soc Lond B Biol Sci, 362, 1887-1925.  
16778797 B.Chavan, J.M.Gillbro, H.Rokos, and K.U.Schallreuter (2006).
GTP cyclohydrolase feedback regulatory protein controls cofactor 6-tetrahydrobiopterin synthesis in the cytosol and in the nucleus of epidermal keratinocytes and melanocytes.
  J Invest Dermatol, 126, 2481-2489.  
17032654 B.El Yacoubi, S.Bonnett, J.N.Anderson, M.A.Swairjo, D.Iwata-Reuyl, and Crécy-Lagard (2006).
Discovery of a new prokaryotic type I GTP cyclohydrolase family.
  J Biol Chem, 281, 37586-37593.  
17057711 I.Tegeder, M.Costigan, R.S.Griffin, A.Abele, I.Belfer, H.Schmidt, C.Ehnert, J.Nejim, C.Marian, J.Scholz, T.Wu, A.Allchorne, L.Diatchenko, A.M.Binshtok, D.Goldman, J.Adolph, S.Sama, S.J.Atlas, W.A.Carlezon, A.Parsegian, J.Lötsch, R.B.Fillingim, W.Maixner, G.Geisslinger, M.B.Max, and C.J.Woolf (2006).
GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.
  Nat Med, 12, 1269-1277.  
16632608 P.Hänzelmann, and H.Schindelin (2006).
Binding of 5'-GTP to the C-terminal FeS cluster of the radical S-adenosylmethionine enzyme MoaA provides insights into its mechanism.
  Proc Natl Acad Sci U S A, 103, 6829-6834.
PDB codes: 2fb2 2fb3
16115872 J.Ren, M.Kotaka, M.Lockyer, H.K.Lamb, A.R.Hawkins, and D.K.Stammers (2005).
GTP cyclohydrolase II structure and mechanism.
  J Biol Chem, 280, 36912-36919.
PDB codes: 2bz0 2bz1
16010344 M.Fischer, and A.Bacher (2005).
Biosynthesis of flavocoenzymes.
  Nat Prod Rep, 22, 324-350.  
15767583 S.G.Van Lanen, J.S.Reader, M.A.Swairjo, Crécy-Lagard, B.Lee, and D.Iwata-Reuyl (2005).
From cyclohydrolase to oxidoreductase: discovery of nitrile reductase activity in a common fold.
  Proc Natl Acad Sci U S A, 102, 4264-4269.  
15159566 G.Bader, M.Gomez-Ortiz, C.Haussmann, A.Bacher, R.Huber, and M.Fischer (2004).
Structure of the molybdenum-cofactor biosynthesis protein MoaB of Escherichia coli.
  Acta Crystallogr D Biol Crystallogr, 60, 1068-1075.
PDB code: 1r2k
15502869 L.I.Leichert, and U.Jakob (2004).
Protein thiol modifications visualized in vivo.
  PLoS Biol, 2, e333.  
15292175 M.A.Kolinsky, and S.S.Gross (2004).
The mechanism of potent GTP cyclohydrolase I inhibition by 2,4-diamino-6-hydroxypyrimidine: requirement of the GTP cyclohydrolase I feedback regulatory protein.
  J Biol Chem, 279, 40677-40682.  
15180982 P.Hänzelmann, H.L.Hernández, C.Menzel, R.García-Serres, B.H.Huynh, M.K.Johnson, R.R.Mendel, and H.Schindelin (2004).
Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis.
  J Biol Chem, 279, 34721-34732.  
14717702 T.Suzuki, H.Kurita, and H.Ichinose (2004).
GTP cyclohydrolase I utilizes metal-free GTP as its substrate.
  Eur J Biochem, 271, 349-355.  
14660404 A.He, and J.P.Rosazza (2003).
GTP cyclohydrolase I: purification, characterization, and effects of inhibition on nitric oxide synthase in nocardia species.
  Appl Environ Microbiol, 69, 7507-7513.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.