Cofactors

There are no Cofactors for this Enzyme

Reaction Mechanism

GTP cyclohydrolase I By Reference

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.




• Summary
• Step 1
• Step 2
• Step 3
• Step 4
• Step 5
• Step 6
• Step 7
• Step 8
• Step 9
• Step 10
• Products

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.



Products.

The products of the reaction.

View Reaction Mechanisms in M-CSA

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

  View all in Brenda
• Temperature

  Organism	Temperature Range	Comment
  Geobacillus stearothermophilus	38 - 78	half-maximal activity at

• pH

  Organism	pH Range	Comment
  Plasmodium falciparum	7 - 11

Associated Proteins

Citations

• Catecholamines and Parkinson's disease: tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: a historical overview.
• Expansion of GTP cyclohydrolase I copy number in malaria parasites resistant to a pyrimidine biosynthesis inhibitor
• Expression of Concern. Shuangxi Wang, Jian Xu, Ping Song, Benoit Viollet, and Ming-Hui Zou. In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I. Diabetes 2009;58:1893-1901. DOI: 10.2337/db09-0267. PMID: 19528375. PMCID: PMC2712774.
• Natural variation of folate content in cowpea (Vigna unguiculata) germplasm and its correlation with the expression of the GTP cyclohydrolase I coding gene
• GTP Cyclohydrolase I as a Potential Drug Target: New Insights into Its Allosteric Modulation via Normal Mode Analysis.
• A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I.
• Endothelium-Specific GTP Cyclohydrolase I Overexpression Restores Endothelial Function in Aged Mice.
• Early-onset autosomal dominant GTP-cyclohydrolase I deficiency: Diagnostic delay and residual motor signs.
• Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP.
• Inhibition of Brain GTP Cyclohydrolase I Attenuates 3-Nitropropionic Acid-Induced Striatal Toxicity: Involvement of Mas Receptor/PI3k/Akt/CREB/ BDNF Axis.
• GTP cyclohydrolase I activity from Rickettsia monacensis strain Humboldt, a rickettsial endosymbiont of Ixodes pacificus.