Enzyme - GTP cyclohydrolase I

Alternative Name(s)

There are no alternative names for this Enzyme

Catalytic Activity

GTP + H2O = 7,8-dihydroneopterin 3'-triphosphate + formate + H(+)


There are no Cofactors for this Enzyme

Reaction Mechanism

    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.

    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
    AA Uniprot Uniprot Resid PDB PDB Resid
    His P0A6T5 114 1fbx 113
    His P0A6T5 180 1fbx 179
    Glu P0A6T5 112 1fbx 111
    His P0A6T5 113 1fbx 112
    Gln P0A6T5 152 1fbx 151
    Cys P0A6T5 111 1fbx 110
    Cys P0A6T5 182 1fbx 181
    Step Components

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

    Step 1.

    Zinc activated water initiates a nucleophilic attack on the C8 of the substrate in an aromatic addition reaction. The nitrogen, N7, which receives the lone pair of electrons gains a proton from His112.

    Step 2.

    His179 deprotonates the added hydroxyl group, cleaving the C8-N9 bond in an elimination which results in the cleavage of the C1-O4 bond in the ribose ring and concomitant deprotonation of His112 by O4.

    Step 3.

    His112 deprotonates the newly formed hydroxyl group, which initiates the reformation of the ribose ring in a nucleophilic addition reaction, which causes the N9 to deprotonate His179.

    Step 4.

    His179 acts as a general base, deprotonating water, which is activated by zinc, this hydroxide then initiates a nucleophilic attack on the amide carbon of the intermediate in a substitution reaction which eliminates formate.

    Step 5.

    First step in the Amadori Rearrangement. His112 donates a proton to the intermediate.

    Step 6.

    Second step of the Amadori Rearrangement . Tautomerisation of the N=C-C bonds.

    Step 7.

    Next step of the Amadori Rearrangement. Keto-enol tautomerisation.

    Step 8.

    Final step of the Amadori Rearrangement. N7 initiates a nucleophilic attack on the carbonyl carbon, forming the new six-membered ring.

    Step 9.

    Water is eliminated, forming a new double bond which extends the conjugation across the molecule.

    Step 10.

    Inferred return step in which His179 and 112 are reprotonated from bulk solvent water molecules, and the activated water molecule zinc ligand is regenerated.


    The products of the reaction.

Reaction Parameters

  • Kinetic Parameters
    Organism KM Value [mM] Substrate Comment
    Bacillus subtilis 0.004 GTP
    Nocardia iowensis 0.007 GTP recombinant enzyme expressed in Escherichia coli
    Neisseria gonorrhoeae 0.00915 GTP pH and temperature not specified in the publication
    Plasmodium falciparum 0.0126 GTP at pH 7.8 and 37°C
    Mus musculus 0.0173 GTP
  • Temperature
    Organism Temperature Range Comment
    Geobacillus stearothermophilus 38 - 78 half-maximal activity at
  • pH
    Organism pH Range Comment
    Plasmodium falciparum 7 - 11

Associated Proteins

Protein name Organism
GTP cyclohydrolase FolE2 Bacillus subtilis (strain 168)
GTP cyclohydrolase 1 type 2 Helicobacter pylori (strain ATCC 700392 / 26695)
GTP cyclohydrolase 1 Human
GTP cyclohydrolase FolE2 1 Burkholderia cenocepacia (strain HI2424)
GTP cyclohydrolase FolE2 2 Burkholderia cenocepacia (strain HI2424)