GTP cyclohydrolase I

GTP cyclohydrolase 1

PDB rendering based on 1fb1.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1FB1

Identifiers

Symbols

GCH1 ; DYT14; DYT5; DYT5a; GCH; GTP-CH-1; GTPCH1; HPABH4B

External IDs

OMIM: 600225 MGI: 95675 HomoloGene: 132 GeneCards: GCH1 Gene

EC number

3.5.4.16

Gene ontology
Molecular function	• GTP cyclohydrolase I activity • calcium ion binding • protein binding • GTP binding • zinc ion binding • GTP-dependent protein binding • protein homodimerization activity • coenzyme binding
Cellular component	• nucleus • nucleoplasm • cytoplasm • cytosol • cytoplasmic vesicle • nuclear membrane • protein complex
Biological process	• tetrahydrobiopterin biosynthetic process • nitric oxide biosynthetic process • regulation of blood pressure • regulation of lung blood pressure • response to lipopolysaccharide • response to interferon-gamma • response to tumor necrosis factor • 7,8-dihydroneopterin 3'-triphosphate biosynthetic process • vasodilation • dopamine biosynthetic process • pteridine-containing compound biosynthetic process • small molecule metabolic process • negative regulation of blood pressure • nitric oxide metabolic process • tetrahydrofolate biosynthetic process • response to pain • neuromuscular process controlling posture • regulation of nitric-oxide synthase activity • positive regulation of nitric-oxide synthase activity • protein homooligomerization • protein heterooligomerization
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 14:
54.84 – 54.9 Mb

Chr 14:
47.15 – 47.19 Mb

PubMed search

GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH₂-3'-TP).

Gene

GTPCH is encoded by the gene GCH1. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all of the variants give rise to a functional enzyme.^[1]

Clinical significance

Mutations in this gene are associated with malignant phenylketonuria (PKU) and hyperphenylalaninemia (HPA), as well as GTP cyclohydrolase I deficiency.^[1] Deficiency of GTP cyclohydrolase I can occur in a recessive and in a dominant form and lead to a lack of certain neurotrasmitters (dopamine, norepinephrine, epinephrine and serotonin). The dominant form, with mutation in only one of the two alleles for GTP cyclohydrolase I, causes dopamine-responsive dystonia, characterized by childhood-onset dystonia. Patients with the recessive form have mutations in both alleles for GTP cyclohydrolase I. Patients present with developmental delays and neurological dysfunction with trunk hypotonia, hypertonia of the extremities, abnormal movements, tremors, convulsions, and sometimes autonomic dysfunction. ^[2] Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). ^[3]

Function

The chemical reaction performed by GTPCH. The important carbons relative to the transformation are numbered for reference.

Identifiers

Databases

PDB structures

AmiGO / EGO

Search
PMC	articles
PubMed	articles
NCBI	proteins

The transcribed protein is the first and rate-limiting enzyme in tetrahydrobiopterin (THB, BH₄) biosynthesis, catalyzing the conversion of GTP into 7,8-DHNP-3'-TP. THB is an essential cofactor required by the aromatic amino acid hydroxylase (AAAH) and nitric oxide synthase (NOS) enzymes in the biosynthesis of the monoamine neurotransmitters serotonin (5-hydroxytryptamine (5-HT)), melatonin, dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), and nitric oxide (NO), respectively.

References

1 2 "Entrez Gene: GCH1 GTP Cyclohydrolase 1 (DOPA-Responsive Dystonia).".
↑ Longo N (June 2009). "Disorders of biopterin metabolism". J Inherit Metab Dis 32 (2): 333–342. doi:10.1007/s10545-009-1067-2. PMID 19234759.
↑ "Patient registry".

External links

GTP Cyclohydrolase I at the US National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NCBI/NIH/UW entry on GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia

PDB gallery

1fb1: CRYSTAL STRUCTURE OF HUMAN GTP CYCLOHYDROLASE I

1is7: Crystal structure of rat GTPCHI/GFRP stimulatory complex

1is8: Crystal structure of rat GTPCHI/GFRP stimulatory complex plus Zn

1wpl: Crystal structure of the inhibitory form of rat GTP cyclohydrolase I/GFRP complex

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

Metabolism of vitamins, coenzymes, and cofactors

Fat soluble vitamins

Vitamin A	Retinol binding protein

Vitamin E	Alpha-tocopherol transfer protein

Vitamin D	liver (Sterol 27-hydroxylase or CYP27A1) renal (25-Hydroxyvitamin D₃ 1-alpha-hydroxylase or CYP27B1) degradation (1,25-Dihydroxyvitamin D₃ 24-hydroxylase or CYP24A1)

Vitamin K	Vitamin K epoxide reductase

Water soluble vitamins

Thiamine (B₁)

Thiamine diphosphokinase

Niacin (B₃)

Pantothenic acid (B₅)

Pantothenate kinase

Folic acid (B₉)

Dihydropteroate synthase Dihydrofolate reductase Serine hydroxymethyltransferase

Methylenetetrahydrofolate reductase

Vitamin B₁₂

Vitamin C

L-gulonolactone oxidase

Riboflavin (B₂)

Riboflavin kinase

Nonvitamin cofactors

Tetrahydrobiopterin

GTP cyclohydrolase I 6-pyruvoyltetrahydropterin synthase Sepiapterin reductase

PCBD1 PTS QDPR

Molybdenum cofactor

Hydrolases: carbon-nitrogen non-peptide (EC 3.5)

3.5.1: Linear amides / Amidohydrolases	Asparaginase Glutaminase Urease Biotinidase Aspartoacylase Ceramidase Aspartylglucosaminidase Fatty acid amide hydrolase Histone deacetylase Sirtuin

3.5.2: Cyclic amides/ Amidohydrolases	Barbiturase Beta-lactamase

3.5.3: Linear amidines/ Ureohydrolases	Arginase Agmatinase Protein-arginine deiminase

3.5.4: Cyclic amidines/ Aminohydrolases	Guanine deaminase Adenosine deaminase AMP deaminase Inosine monophosphate synthase DCMP deaminase GTP cyclohydrolase I Cytidine deaminase AICDA Activation-induced cytidine deaminase

3.5.5: Nitriles/ Aminohydrolases	Nitrilase

3.5.99: Other	Riboflavinase Thiaminase II

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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