GCHFR

Summary

GCHFR (GTP cyclohydrolase I feedback regulator, HGNC:4194) is a protein-coding gene on chromosome 15q15.1, encoding GTP cyclohydrolase 1 feedback regulatory protein (P30047). Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1.

GTP cyclohydrolase I feedback regulatory protein binds to and mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase I. The regulatory protein, GCHFR, consists of a homodimer. It is postulated that GCHFR may play a role in regulating phenylalanine metabolism in the liver and in the production of biogenic amine neurotransmitters and nitric oxide.

Source: NCBI Gene 2644 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 2 total
• MANE Select transcript: NM_005258

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4194
Approved symbol	GCHFR
Name	GTP cyclohydrolase I feedback regulator
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Aliases	GFRP, HsT16933
Ensembl gene	ENSG00000137880
Ensembl biotype	protein_coding
OMIM	602437
Entrez	2644

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000260447, ENST00000558467, ENST00000558670, ENST00000559445, ENST00000559932, ENST00000561160

RefSeq mRNA: 1 — MANE Select: NM_005258 NM_005258

CCDS: CCDS10064

Canonical transcript exons

ENST00000260447 — 3 exons

Exon	Start	End
ENSE00001100158	40764068	40764216
ENSE00002571628	40767226	40767708
ENSE00003654018	40765827	40765921

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.6531 / max 303.2218, expressed in 1563 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146129	12.9455	1542
146128	0.3684	208
146130	0.3393	118

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.75	gold quality
liver	UBERON:0002107	95.08	gold quality
lower esophagus mucosa	UBERON:0035834	94.41	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.93	gold quality
mucosa of transverse colon	UBERON:0004991	93.46	gold quality
right lung	UBERON:0002167	91.75	gold quality
jejunal mucosa	UBERON:0000399	91.32	gold quality
ileal mucosa	UBERON:0000331	90.89	gold quality
duodenum	UBERON:0002114	90.63	gold quality
esophagus mucosa	UBERON:0002469	90.61	gold quality
adult mammalian kidney	UBERON:0000082	90.02	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.85	gold quality
upper lobe of left lung	UBERON:0008952	89.43	gold quality
small intestine	UBERON:0002108	88.95	gold quality
oral cavity	UBERON:0000167	88.92	gold quality
skin of leg	UBERON:0001511	88.65	gold quality
granulocyte	CL:0000094	88.45	gold quality
skin of abdomen	UBERON:0001416	88.43	gold quality
upper lobe of lung	UBERON:0008948	88.38	gold quality
omental fat pad	UBERON:0010414	88.30	gold quality
peritoneum	UBERON:0002358	88.25	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.16	gold quality
metanephros cortex	UBERON:0010533	87.51	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.01	gold quality
nasal cavity mucosa	UBERON:0001826	86.61	gold quality
left adrenal gland cortex	UBERON:0035825	86.35	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.34	gold quality
minor salivary gland	UBERON:0001830	86.29	gold quality
adipose tissue	UBERON:0001013	86.16	gold quality
zone of skin	UBERON:0000014	85.93	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6653	yes	1838.48
E-HCAD-10	yes	35.04
E-ANND-3	yes	13.32
E-MTAB-8271	yes	7.30
E-HCAD-38	no	285.76
E-MTAB-6142	no	46.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FEV

miRNA regulators (miRDB)

8 targeting GCHFR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-6856-3P	96.47	66.27	781
HSA-MIR-3918	96.13	64.65	1300

Literature-anchored findings (GeneRIF, showing 12)

• crystal structure (PMID:11580249)
• Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein (PMID:11799107)
• allosteric regulation of GTPCH-I activity in the cardiovascular system maybe an important mechanism regulating BH4 levels through GTPCH-I feedback regulatory protein signaling (PMID:15649650)
• GFRP/GTPCHI axis functions in epidermal keratinocytes and melanocytes in the cytosol and nucleus. (PMID:16778797)
• GCH1 mutations in Japanese patients with DYT5 dystonia. In some of them, the GCH1 enzyme activity was proved to be impaired. (PMID:17101830)
• The co-expression of GTP cyclohydrolase I (GCHI) with tyrosine hydroxylase (TH) indicates that TH is indeed active in human neurosecretory neurons. (PMID:17135716)
• Demonstrate role for GFRP in regulating iNOS-mediated NO synthesis and suggest that the allosteric regulation of GTP-CH1 activity by GFRP may be an important mechanism regulating BH(4) and NO levels in vivo. (PMID:18372436)
• 6BH(4) de novo synthesis is controlled by H(2)O(2) in a concentration-dependent manner, but H(2)O(2)-mediated oxidation does not affect the functionality of the GTPCHI/GFRP complex. (PMID:19101819)
• Studies provide a new mechanism for regulation of endothelial GTPCH-1 by its phosphorylation and interplay with GFRP. (PMID:19926872)
• homozygous individuals for the TT haplotype were less likely to respond to the SSRI fluoxetine than to the nortriptyline suggesting a biological process through which GCHFR promoter variants might influence antidepressant response. (PMID:20351752)
• A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I. (PMID:33229582)
• Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP. (PMID:33387654)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gchfr	ENSDARG00000098588
mus_musculus	Gchfr	ENSMUSG00000046814
rattus_norvegicus	Gchfr	ENSRNOG00000012290
caenorhabditis_elegans		WBGENE00044736

Protein

Protein identifiers

GTP cyclohydrolase 1 feedback regulatory protein — P30047 (reviewed: P30047)

Alternative names: GTP cyclohydrolase I feedback regulatory protein, p35

All UniProt accessions (4): P30047, A0A087WTI4, H0YNM1, H0YNX7

UniProt curated annotations — full annotation on UniProt →

Function. Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1. This inhibition is reversed by L-phenylalanine.

Subunit / interactions. Homopentamer. Forms a complex with GCH1 where a GCH1 homodecamer is sandwiched by two GFRP homopentamers. Interacts with GCH1.

Subcellular location. Nucleus. Nucleus membrane. Cytoplasm. Cytosol.

Tissue specificity. In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level).

Similarity. Belongs to the GFRP family.

Isoforms (2)

UniProt ID	Names	Canonical?
P30047-1	1	yes
P30047-2	2

RefSeq proteins (1): NP_005249* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009112	GTP_CycHdrlase_I_reg	Family
IPR036717	GFRP_sf	Homologous_superfamily

Pfam: PF06399

UniProt features (13 total): strand 8, helix 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7ALC	X-RAY DIFFRACTION	1.73
7AL9	X-RAY DIFFRACTION	1.75
7ALA	X-RAY DIFFRACTION	1.85
7ALB	X-RAY DIFFRACTION	1.98
7ACC	X-RAY DIFFRACTION	2.04
7ALQ	X-RAY DIFFRACTION	2.21
6Z85	ELECTRON MICROSCOPY	2.9
6Z80	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30047-F1	97.88	0.97

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1474151	Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation

MSigDB gene sets: 174 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, GOBP_REACTIVE_NITROGEN_SPECIES_METABOLIC_PROCESS, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, HOSHIDA_LIVER_CANCER_LATE_RECURRENCE_DN, MODULE_88, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, GOCC_NEURON_PROJECTION, SASAKI_ADULT_T_CELL_LEUKEMIA, WESTON_VEGFA_TARGETS, WESTON_VEGFA_TARGETS_3HR, GOCC_NUCLEAR_ENVELOPE

GO Biological Process (3): negative regulation of biosynthetic process (GO:0009890), regulation of nitric oxide biosynthetic process (GO:0045428), negative regulation of small molecule metabolic process (GO:0062014)

GO Molecular Function (5): enzyme inhibitor activity (GO:0004857), GTP cyclohydrolase binding (GO:0044549), GTP cyclohydrolase I regulator activity (GO:0060308), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), dendrite (GO:0030425), nuclear membrane (GO:0031965), melanosome (GO:0042470), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of biosynthetic process	2
negative regulation of metabolic process	2
catalytic activity	2
enzyme regulator activity	2
biosynthetic process	1
nitric oxide biosynthetic process	1
regulation of nitric oxide metabolic process	1
small molecule metabolic process	1
regulation of small molecule metabolic process	1
molecular function inhibitor activity	1
enzyme binding	1
GTP cyclohydrolase I activity	1
GTP cyclohydrolase binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
neuron projection	1
dendritic tree	1
nucleus	1
nuclear envelope	1
organelle membrane	1
pigment granule	1

Protein interactions and networks

STRING

448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCHFR	GCH1	P30793	821
GCHFR	SPR	P35270	706
GCHFR	QDPR	P09417	668
GCHFR	PCBD1	P61457	603
GCHFR	DNAJC12	Q9UKB3	558
GCHFR	PAH	P00439	491
GCHFR	PTS	Q03393	448
GCHFR	GPR143	P51810	362
GCHFR	STUB1	Q9UNE7	347
GCHFR	AGMO	Q6ZNB7	324
GCHFR	SLC22A3	O75751	319
GCHFR	RPP21	Q9H633	312
GCHFR	PCBD2	Q9H0N5	306
GCHFR	ADRA1B	P35368	297
GCHFR	DHFR	P00374	296
GCHFR	MLANA	Q16655	296

IntAct

10 interactions, top by confidence:

A	B	Type	Score
SPINK2	STRN	psi-mi:“MI:0914”(association)	0.530
FXYD1	GCHFR	psi-mi:“MI:0914”(association)	0.530
GCH1	GCHFR	psi-mi:“MI:0915”(physical association)	0.370
GCHFR	OBSL1	psi-mi:“MI:0914”(association)	0.350
SHARPIN	ZNF609	psi-mi:“MI:0914”(association)	0.350
FXYD1	SPINK4	psi-mi:“MI:0914”(association)	0.350
CCL4	PEX14	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): GCHFR (Affinity Capture-RNA), GCHFR (Affinity Capture-MS), CAMKK2 (Affinity Capture-MS), CBFB (Affinity Capture-MS), GCHFR (Affinity Capture-MS), PUSL1 (Affinity Capture-MS), NEBL (Affinity Capture-MS), EIF4G1 (Affinity Capture-MS), OBSL1 (Affinity Capture-MS), DOCK11 (Affinity Capture-MS), HBS1L (Affinity Capture-MS), IRF2BP2 (Affinity Capture-MS), GCHFR (Affinity Capture-RNA), GCHFR (Affinity Capture-MS), CAMKK2 (Affinity Capture-MS)

ESM2 similar proteins: A2VE39, A8BQB4, D2HRF1, O43617, O55013, O75694, P17707, P30047, P35573, P35574, P42898, P48603, P50243, P70552, P99025, Q08DS5, Q0IJ33, Q1MTD3, Q2HJG5, Q2M146, Q2PQH8, Q32L41, Q3B8G0, Q40073, Q4IBU4, Q5BLF0, Q5I598, Q5R981, Q5RC82, Q5U1Z2, Q5U2Z5, Q60HE5, Q6GM84, Q6GNS3, Q6NVA8, Q6P2Z6, Q6PBT6, Q6WRS2, Q6Z9U7, Q7K556

Diamond homologs: P30047, P70552, P99025, Q32L41, Q6GM84, Q6NVA8, Q6PBT6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
GCHFR	“down-regulates activity”	GCH1	binding
sapropterin	“up-regulates activity”	GCHFR	“chemical activation”
phenylalanine	“down-regulates activity”	GCHFR	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

2 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

456 predictions. Top by Δscore:

Variant	Effect	Δscore
15:40765823:GCAG:G	acceptor_loss	1.0000
15:40765918:ACTT:A	donor_gain	1.0000
15:40765919:CTT:C	donor_gain	1.0000
15:40765922:G:GG	donor_gain	1.0000
15:40764212:GCATG:G	donor_gain	0.9900
15:40764215:TG:T	donor_gain	0.9900
15:40764216:GG:G	donor_gain	0.9900
15:40764217:G:GA	donor_loss	0.9900
15:40764217:G:GG	donor_gain	0.9900
15:40764218:T:A	donor_loss	0.9900
15:40765825:A:AG	acceptor_gain	0.9900
15:40765825:AG:A	acceptor_gain	0.9900
15:40765826:G:GG	acceptor_gain	0.9900
15:40765826:GG:G	acceptor_gain	0.9900
15:40765826:GGA:G	acceptor_gain	0.9900
15:40765917:AACTT:A	donor_gain	0.9900
15:40765918:ACTTG:A	donor_loss	0.9900
15:40765920:TT:T	donor_gain	0.9900
15:40765921:TGTA:T	donor_loss	0.9900
15:40765922:G:C	donor_loss	0.9900
15:40765923:T:A	donor_loss	0.9900
15:40765924:AAG:A	donor_loss	0.9900
15:40767220:TTGCA:T	acceptor_loss	0.9900
15:40767221:TGCAG:T	acceptor_loss	0.9900
15:40767222:GCAG:G	acceptor_loss	0.9900
15:40767223:CAGT:C	acceptor_loss	0.9900
15:40767224:A:AG	acceptor_gain	0.9900
15:40767224:A:AT	acceptor_loss	0.9900
15:40767225:G:GA	acceptor_gain	0.9900
15:40767225:GT:G	acceptor_gain	0.9900

AlphaMissense

543 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:40767329:T:A	W79R	0.997
15:40767329:T:C	W79R	0.997
15:40767273:T:C	L60P	0.995
15:40767261:T:A	V56D	0.994
15:40767252:C:A	P53H	0.993
15:40765846:T:A	V19E	0.991
15:40765848:G:C	G20R	0.991
15:40767264:T:C	L57P	0.991
15:40767336:T:C	L81P	0.991
15:40765849:G:A	G20D	0.990
15:40767273:T:A	L60Q	0.989
15:40764199:A:C	S7R	0.988
15:40764201:C:A	S7R	0.988
15:40764201:C:G	S7R	0.988
15:40765834:G:A	G15D	0.988
15:40765833:G:C	G15R	0.987
15:40765849:G:T	G20V	0.987
15:40767233:T:G	Y47D	0.987
15:40767314:G:C	G74R	0.987
15:40765885:T:A	L32Q	0.986
15:40767252:C:G	P53R	0.986
15:40767287:T:C	F65L	0.986
15:40767289:C:A	F65L	0.986
15:40767289:C:G	F65L	0.986
15:40767264:T:A	L57Q	0.985
15:40767273:T:G	L60R	0.985
15:40767315:G:T	G74V	0.984
15:40765876:T:C	M29T	0.983
15:40765885:T:C	L32P	0.983
15:40767288:T:C	F65S	0.983

dbSNP variants (sampled 300 via entrez): RS1000690905 (15:40763204 G>A), RS1000790011 (15:40763431 G>A), RS1001517486 (15:40767116 C>A,T), RS1002575815 (15:40768125 G>A,C), RS1002702436 (15:40762706 G>C), RS1003122191 (15:40762411 G>A,T), RS1003720702 (15:40763836 G>C), RS1004117474 (15:40764097 G>A), RS1004682172 (15:40765015 T>C), RS1004810486 (15:40765464 TCTCA>T), RS1005593831 (15:40762482 T>C), RS1005674380 (15:40766859 G>A,T), RS1005684116 (15:40766539 G>C), RS1006787564 (15:40763128 AG>A), RS1007161682 (15:40768187 G>C)

Disease associations

OMIM: gene MIM:602437 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006613_63	Triglycerides	4.000000e-08
GCST008559_8	Anxiety and stress-related disorders	7.000000e-07
GCST010725_23	Malaria	2.000000e-06
GCST010725_38	Malaria	3.000000e-06
GCST010725_80	Malaria	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0010098	stress-related disorder

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	4
Benzo(a)pyrene	decreases expression, decreases methylation	3
entinostat	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Nickel	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	increases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases methylation, decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
avobenzone	increases expression	1
CGP 52608	increases reaction, affects binding	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.