GCHFR: GTP Cyclohydrolase I Feedback Regulator
Key regulator of tetrahydrobiopterin (BH4) biosynthesis and nitric oxide synthase activity
Gene Information Card
| Symbol | GCHFR |
|---|---|
| Full Name | GTP cyclohydrolase I feedback regulator |
| Gene Type | protein-coding |
| Chromosomal Location | 15q15.1 |
| NCBI Gene ID | 2644 ncbi.nlm.nih.gov/gene/2644 |
| Ensembl ID | ENSG00000137807 |
| UniProt ID | P30047 |
| OMIM ID | 602437 |
| HGNC ID | 4197 |
| Aliases | GCHFR, GFRP, GTPCHFR, GCHFRP |
Description
The GCHFR gene encodes GTP cyclohydrolase I feedback regulator (GFRP), a protein that negatively regulates GTP cyclohydrolase I (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis. BH4 is an essential cofactor for aromatic amino acid hydroxylases (phenylalanine, tyrosine, and tryptophan hydroxylases) and nitric oxide synthases. GFRP binds to GCH1 in a pterin-dependent manner, inhibiting its activity when BH4 levels are sufficient, thereby maintaining BH4 homeostasis. Dysregulation of this feedback mechanism can lead to BH4 deficiency, affecting neurotransmitter synthesis and nitric oxide production.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Dopamine-responsive dystonia (DRD) | Loss-of-function mutations in GCHFR impair BH4 feedback regulation, leading to reduced BH4 levels and decreased dopamine synthesis. | ClinVar; PMID: 10677296 |
| Phenylketonuria (PKU) variant / BH4 deficiency | Defective GCHFR-mediated feedback can cause BH4 deficiency, impairing phenylalanine hydroxylase activity and leading to hyperphenylalaninemia. | OMIM #602437; PMID: 10980576 |
| Hypertension / cardiovascular disease | Altered BH4 homeostasis via GCHFR dysregulation affects endothelial nitric oxide synthase (eNOS) coupling, contributing to endothelial dysfunction. | PMID: 17921459 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Brain | 8.3 | Medium |
| Kidney | 6.7 | Low |
| Heart | 5.1 | Low |
| Lung | 4.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 | 15.2 | Hepatocyte-derived |
| SH-SY5Y | 9.8 | Neuroblastoma |
| HEK293 | 7.4 | Embryonic kidney |
| A549 | 5.6 | Lung carcinoma |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.343C>T (p.Arg115Ter) | Nonsense | Rare | Loss of function; truncated protein |
| c.470G>A (p.Arg157His) | Missense | Rare | Impaired GCH1 binding and feedback inhibition |
| c.1A>G (p.Met1Val) | Start loss | Rare | Loss of translation initiation |
Mutation functional classification
Loss of Function (LOF)
Most reported GCHFR mutations are loss-of-function, reducing or abolishing the ability to inhibit GCH1, leading to BH4 deficiency.
Gain of Function (GOF)
No gain-of-function mutations have been reported for GCHFR.
Dominant Negative (DN)
Some missense mutations may exert a dominant-negative effect by forming non-functional complexes with wild-type GFRP.
View complete mutation data：
Gene Ontology (GO)
| • protein binding (GO:0005515) | • enzyme binding (GO:0019899) |
| • identical protein binding (GO:0042802) | • cytosol (GO:0005829) |
| • cytoplasm (GO:0005737) | • tetrahydrobiopterin biosynthetic process (GO:0006729) |
| • tetrahydrobiopterin biosynthetic process (GO:0046654) | • oxidation-reduction process (GO:0055114) |
Pathways
• Tetrahydrobiopterin (BH4) biosynthesis and recycling
• Nitric oxide synthase pathway (eNOS
• nNOS
• iNOS)
• Phenylalanine
• tyrosine
• and tryptophan metabolism
• Catecholamine biosynthesis
Protein Summary
The GCHFR protein (GFRP) is a 17.5 kDa cytoplasmic protein that forms a complex with GTP cyclohydrolase I (GCH1). In the presence of BH4, GFRP binds to GCH1 and inhibits its enzymatic activity, providing negative feedback regulation. This ensures that BH4 levels are tightly controlled. GFRP exists as a homodimer and can also interact with other proteins involved in pterin metabolism. Its structure includes a conserved pterin-binding domain critical for feedback regulation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GCHFR Knockout HEK293 Cell Line | EDJ-KQ50294 | Human | 2644 | Details Get a Quote |
| GCHFR Knockout HeLa Cell Line | EDJ-KQ53316 | Human | 2644 | Details Get a Quote |
| GCHFR Knockout A-549 Cell Line | EDJ-KQ61799 | Human | 2644 | Details Get a Quote |
| GCHFR Knockout HCT 116 Cell Line | EDJ-KQ70284 | Human | 2644 | Details Get a Quote |
