GTP cyclohydrolase I

 

GTP cyclohydrolase I catalyses the complex reaction which converts GTP to dihydroneopterin triphosphate. This is the first step of a pathway, which in plants and micro-organisms leads to tetrahydrofolate production, and in animals leads to tetrahydrobiopterin production. Tetrahydrobiopterin is biologically important as it serves as a cofactor in the production of catecholamines and nitric oxide. Genetic defects in GTP cyclohydrolase can therefore lead to severe neurological disorders. Enzymes involved in the formation of tetrahydrofolate are also important anti-infection drug targets.

Allosteric enzyme. Activity is modulated by K+, divalent cations, UTP, and tetrahydrobiopterin. Tetrahydrobiopterin is an inhibitor of this enzyme.

 

Reference Protein and Structure

Sequence
P0A6T5 UniProt (3.5.4.16) IPR001474 (Sequence Homologues) (PDB Homologues)
Biological species
Escherichia coli K-12 (Bacteria) Uniprot
PDB
1fbx - CRYSTAL STRUCTURE OF ZINC-CONTAINING E.COLI GTP CYCLOHYDROLASE I (2.8 Å) PDBe PDBsum 1fbx
Catalytic CATH Domains
3.30.1130.10 CATHdb (see all for 1fbx)
Cofactors
Zinc(2+) (1), Water (2) Metal MACiE
Click To Show Structure

Enzyme Reaction (EC:3.5.4.16)

GTP(4-)
CHEBI:37565ChEBI
+
water
CHEBI:15377ChEBI
formic acid
CHEBI:30751ChEBI
+
7,8-dihydroneopterin 3'-triphosphate(4-)
CHEBI:58462ChEBI
Alternative enzyme names: GTP 8-formylhydrolase, GTP cyclohydrolase, Dihydroneopterin triphosphate synthase, Guanosine triphosphate 8-deformylase, Guanosine triphosphate cyclohydrolase,

Enzyme Mechanism

Introduction

GTP cyclohydrolase I contains an essential zinc cation, thought to act as a Lewis acid, activating a water molecule towards hydrolytic opening of the imidazole ring of GTP. Three residues, Cys110, Cys181, His112 coordinate to this metal, with one vacant coordination position available to the hydrolytic water.

The reaction is initiated by His179, which acts as an acid and donates a proton to N7. The positively charged ring is now susceptible to nucleophilic attack at C8 by a water molecule. His112 protonates the bridging O of the furanose ring which leads to the opening of the furanose ring. Amadori rearrangement of this intermediate and proton abstraction by a base thought to be Ser135 leads to another intermediate. The last stage of the reaction, the closure of the pterin ring system is thought to be non-enzymatically catalysed either on the protein surface, or in solution.

Catalytic Residues Roles

UniProt PDB* (1fbx)
His180 His179A Acts as a general acid/base via an active site water molecule. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Glu112 Glu111A Activates His112 via a water molecule. hydrogen bond acceptor, electrostatic stabiliser
His113 His112A Acts as a general acid base. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Gln152 Gln151A Activates His179. hydrogen bond acceptor, electrostatic stabiliser
His114, Cys111, Cys182 His113A, Cys110A, Cys181A Form the Zn(II) binding site. metal ligand
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

aromatic bimolecular nucleophilic addition, overall reactant used, intermediate formation, proton transfer, bimolecular elimination, decyclisation, intramolecular nucleophilic addition, cyclisation, bimolecular nucleophilic substitution, overall product formed, unimolecular elimination by the conjugate base, rate-determining step, intramolecular rearrangement, keto-enol tautomerisation, intramolecular elimination

References

  1. Rebelo J et al. (2003), J Mol Biol, 326, 503-516. Biosynthesis of Pteridines. Reaction Mechanism of GTP Cyclohydrolase I. DOI:10.1016/s0022-2836(02)01303-7. PMID:12559918.
  2. Gräwert T et al. (2013), IUBMB Life, 65, 310-322. Structures and reaction mechanisms of GTP cyclohydrolases. DOI:10.1002/iub.1153. PMID:23457054.
  3. Ren J et al. (2005), J Biol Chem, 280, 36912-36919. GTP Cyclohydrolase II Structure and Mechanism. DOI:10.1074/jbc.m507725200. PMID:16115872.
  4. Tanaka Y et al. (2005), J Biochem, 138, 263-275. Novel Reaction Mechanism of GTP Cyclohydrolase I. High-Resolution X-Ray Crystallography of Thermus thermophilus HB8 Enzyme Complexed with a Transition State Analogue, the 8-Oxoguanine Derivative. DOI:10.1093/jb/mvi120. PMID:16169877.
  5. Lee S et al. (2002), BMB Rep, 35, 255-261. Biochemical Characterization of Oligomerization of Escherichia coli GTP Cyclohydrolase I. DOI:10.5483/bmbrep.2002.35.3.255.
  6. Schramek N et al. (2001), J Biol Chem, 276, 2622-2626. Ring Opening Is Not Rate-limiting in the GTP Cyclohydrolase I Reaction. DOI:10.1074/jbc.m004912200. PMID:11056154.
  7. Auerbach G et al. (2000), Proc Natl Acad Sci U S A, 97, 13567-13572. Zinc plays a key role in human and bacterial GTP cyclohydrolase I. DOI:10.1073/pnas.240463497. PMID:11087827.
  8. Bracher A et al. (1998), J Biol Chem, 273, 28132-28141. Biosynthesis of Pteridines: NMR STUDIES ON THE REACTION MECHANISMS OF GTP CYCLOHYDROLASE I, PYRUVOYLTETRAHYDROPTERIN SYNTHASE, AND SEPIAPTERIN REDUCTASE. DOI:10.1074/jbc.273.43.28132. PMID:9774432.
  9. Nar H et al. (1995), Structure, 3, 459-466. Atomic structure of GTP cyclohydrolase I. DOI:10.1016/s0969-2126(01)00179-4. PMID:7663943.

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond donor
His112A hydrogen bond donor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand
His179A proton donor

Chemical Components

ingold: aromatic bimolecular nucleophilic addition, overall reactant used, intermediate formation, proton transfer

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond acceptor
His112A hydrogen bond donor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand
Gln151A electrostatic stabiliser
Glu111A electrostatic stabiliser, hydrogen bond acceptor
Gln151A hydrogen bond acceptor
His179A proton acceptor
His112A proton donor

Chemical Components

ingold: bimolecular elimination, decyclisation, intermediate formation, proton transfer

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond donor
His112A hydrogen bond acceptor
Glu111A hydrogen bond acceptor
Gln151A hydrogen bond acceptor
Glu111A electrostatic stabiliser
Gln151A electrostatic stabiliser
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand
His179A proton donor
His112A proton acceptor

Chemical Components

ingold: intramolecular nucleophilic addition, cyclisation, intermediate formation, proton transfer

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond acceptor
His112A hydrogen bond donor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand
His179A proton acceptor

Chemical Components

ingold: bimolecular nucleophilic substitution, overall reactant used, overall product formed, intermediate formation, proton transfer

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond acceptor
His112A hydrogen bond donor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand
His112A proton donor
His179A proton donor

Chemical Components

intermediate formation, proton transfer

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond acceptor
His112A hydrogen bond acceptor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand

Chemical Components

ingold: unimolecular elimination by the conjugate base, intermediate formation, rate-determining step

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond acceptor
His112A hydrogen bond acceptor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand

Chemical Components

proton transfer, intramolecular rearrangement, intermediate formation, keto-enol tautomerisation

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond acceptor
His112A hydrogen bond acceptor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand

Chemical Components

proton transfer, intermediate formation, cyclisation, ingold: intramolecular nucleophilic addition

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond donor
His112A hydrogen bond acceptor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand

Chemical Components

intermediate formation, proton transfer, ingold: intramolecular elimination

Catalytic Residues Roles

Residue Roles
His179A hydrogen bond donor
His112A hydrogen bond acceptor
Cys181A metal ligand
Cys110A metal ligand
His113A metal ligand
Glu111A electrostatic stabiliser
Gln151A electrostatic stabiliser
His179A proton acceptor
His112A proton acceptor

Chemical Components

overall product formed, proton transfer

Contributors

Gemma L. Holliday, Gail J. Bartlett, Daniel E. Almonacid, Sophie T. Williams, Anna Waters, Craig Porter