Affinage

GCH1

GTP cyclohydrolase 1 · UniProt P30793

Length
250 aa
Mass
27.9 kDa
Annotated
2026-04-28
100 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCH1 encodes GTP cyclohydrolase I, the rate-limiting enzyme in de novo tetrahydrobiopterin (BH4) biosynthesis from GTP, and thereby controls the cofactor supply for nitric oxide synthases and aromatic amino acid hydroxylases, governing NO production, eNOS coupling, catecholamine synthesis, redox homeostasis, and ferroptosis resistance across vascular, neural, immune, and cancer cell contexts (PMID:25451639, PMID:29596571, PMID:35223839, PMID:34876467). GCH1 is transcriptionally induced by NRF2, PBX1, PRRX2, and EGFR/KRAS signalling and regulated post-transcriptionally by RNA-binding proteins HuR and AUF1 at 3′-UTR AU-rich elements, by miR-206 and miR-124, and post-translationally through the phenylalanine-activated GCH1–GFRP feedback complex and circSEPT9-mediated ubiquitination blockade (PMID:28596000, PMID:30091833, PMID:27826622, PMID:29436714, PMID:31210282, PMID:29963647, PMID:38040194). In macrophages, GCH1-derived BH4 is obligate for iNOS-dependent NO synthesis and NRF2-dependent antioxidant gene induction, yet leukocyte-specific Gch1 deletion paradoxically enhances mycobacterial control through NO-independent inflammatory and metabolic reprogramming (PMID:25451639, PMID:30573728). Loss-of-function mutations in GCH1, including splice-site variants that truncate the protein, cause autosomal-dominant dopa-responsive dystonia (PMID:10732814).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 Medium

    Establishing the molecular basis of dopa-responsive dystonia: splice-site mutations in GCH1 generate frameshifted, truncated polypeptides, directly linking GCH1 loss-of-function to the disease.

    Evidence RT-PCR and sequencing of patient GCH1 mRNA revealing exon skipping and aberrant splicing

    PMID:10732814

    Open questions at the time
    • Single lab report; no enzymatic activity measurement of truncated products
    • Dominant-negative versus haploinsufficiency mechanism not resolved
  2. 2004 Medium

    Functional validation of pathogenic GCH1 mutations: yeast complementation showed specific missense and frameshift mutations abolish or conditionally impair GTP cyclohydrolase I activity, providing a generalizable assay for variant interpretation.

    Evidence In vivo yeast complementation (S. cerevisiae fol2 deletion) of human GCH1 variants

    PMID:15303002

    Open questions at the time
    • No mammalian enzymatic assay performed
    • Heterologous system may miss mammalian-specific regulatory interactions
  3. 2007 Medium

    Demonstrating that common human GCH1 genetic variation modulates NO physiology: a 3′-UTR polymorphism (C+243T) functionally reduced GCH1 expression and associated with renal NO excretion and cardiovascular autonomic traits in a twin study.

    Evidence 3′-UTR reporter assay in transfected cells combined with human twin cohort phenotyping

    PMID:17717598

    Open questions at the time
    • Reporter assay in heterologous cell line; endogenous regulation not confirmed
    • Causal variant versus linkage disequilibrium not fully resolved
  4. 2008 High

    Translating genetic variation to human vascular pathophysiology: a GCH1 haplotype predicted lower vascular GCH1 mRNA, reduced BH4, eNOS uncoupling with superoxide production, and impaired vasodilation in coronary artery disease patients.

    Evidence Direct measurement of GCH1 mRNA, BH4, eNOS-derived superoxide, and vasodilation in human vascular tissue from 347 CAD patients

    PMID:18598896

    Open questions at the time
    • Cross-sectional design; causality from haplotype to disease progression not established
    • No intervention to rescue BH4 in human tissue
  5. 2012 High

    Revealing a non-canonical role for GCH1/BH4 in cardiac autonomic signalling: BH4-deficient hph-1 mice exhibited enhanced β-adrenergic sensitivity and tachycardia due to upregulated β1-adrenoceptor/cAMP signalling, not vagal impairment.

    Evidence hph-1 mouse model with in vivo autonomic pharmacology, stellate ganglion stimulation, β1-adrenoceptor protein quantification, and cAMP assay

    PMID:22241166

    Open questions at the time
    • Mechanism by which BH4 deficiency upregulates β1-adrenoceptor not identified
    • hph-1 is hypomorphic, not null; residual activity may confound
  6. 2014 High

    Definitive demonstration that GCH1-derived BH4 is an obligate iNOS cofactor in macrophages and is required for NRF2-dependent antioxidant gene induction: conditional Gch1 deletion eliminated NO production and selectively impaired NRF2 target genes, while BH4 supplementation rescued both defects.

    Evidence Gch1fl/fl Tie2cre conditional KO macrophages with EPR spin trapping, L-citrulline assay, ROS measurement, and sepiapterin rescue

    PMID:25451639

    Open questions at the time
    • Mechanism linking BH4 to NRF2 transcriptional activation not defined
    • Tie2cre targets both endothelial and hematopoietic lineages
  7. 2014 High

    Establishing GCH1 as essential for embryonic survival: global Gch1 knockout caused embryonic lethality with bradycardia; combined BH4 and L-DOPA supplementation partially rescued, implicating both cofactor and catecholamine pathways.

    Evidence Global Gch1 KO (Sox2cre), embryo BH4 metabolomics, maternal BH4/L-DOPA supplementation rescue

    PMID:25557619

    Open questions at the time
    • Precise cardiac cell-autonomous mechanism of lethality not resolved
    • Incomplete rescue suggests additional BH4-dependent pathways contribute
  8. 2016 Medium

    Identification of post-transcriptional regulators of GCH1: AUF1 was shown to stabilize GCH1 mRNA via 3′-UTR AU-rich elements, and HuR binding to the same region was disrupted by nicotine, reducing GCH1 expression and eNOS coupling in endothelial cells.

    Evidence Luciferase reporter assays for AUF1 and HuR binding to GCH1 3′-UTR; siRNA knockdown; ApoE−/− mouse atherosclerosis model for HuR–nicotine axis

    PMID:27826622 PMID:30091833

    Open questions at the time
    • Whether AUF1 and HuR compete or cooperate at the GCH1 3′-UTR is unknown
    • No structural data on RBP–GCH1 mRNA interaction
  9. 2016 Medium

    Placing GCH1 downstream of PI3K/Akt–Foxo1 and AMPK signalling for eNOS coupling: pharmacological epistasis showed liraglutide induces GCH1 via PI3K/Akt–Foxo1 and metformin upregulates GCH1 via AMPK, each restoring BH4 and NO-dependent endothelial function.

    Evidence Pathway inhibitor dissection (LY294002, compound C, DAHP, L-NAME) with BH4/NO readouts in endothelial cells

    PMID:27217019 PMID:27777063

    Open questions at the time
    • No direct transcription factor binding to GCH1 promoter demonstrated for either pathway
    • Pharmacological inhibitors have off-target effects; genetic confirmation lacking
  10. 2017 Medium

    Establishing the NRF2–GCH1 transcriptional axis: NRF2 was shown to drive GCH1 expression, and GCH1 knockdown abolished NRF2-mediated radioprotection, positioning GCH1 as a key NRF2 antioxidant effector.

    Evidence GCH1 overexpression/knockdown in skin cells and rat irradiation model with BH4, NO, and ROS readouts

    PMID:28596000

    Open questions at the time
    • Direct NRF2 binding to GCH1 promoter (ChIP) not shown in this study
    • Limited to radiation-injury context
  11. 2018 High

    Resolving cell-type contributions to atherogenesis: bone marrow chimeras demonstrated that combined loss of GCH1 in both endothelial cells and leukocytes is required to accelerate atherosclerosis, indicating cooperative BH4-dependent protection from both compartments.

    Evidence Gch1fl/fl Tie2cre × ApoE−/− mice with bone marrow chimeras, VCAM-1 expression, and ex vivo vasodilation

    PMID:29596571

    Open questions at the time
    • Relative contribution of eNOS uncoupling versus macrophage ROS to plaque progression not quantified
    • Tie2cre also deletes Gch1 in some non-endothelial vascular cells
  12. 2018 High

    Revealing NO-independent immune functions of GCH1: leukocyte-specific Gch1 deletion paradoxically enhanced mycobacterial control compared to wild-type, while Nos2−/− mice were susceptible, and transcriptomics showed reprogrammed inflammatory, lysosomal, and metabolic pathways.

    Evidence Gch1fl/fl Tie2cre and Nos2−/− mice with M. tuberculosis infection, RNAseq, human leukocyte validation

    PMID:30573728

    Open questions at the time
    • Specific NO-independent effector mechanism not identified
    • Paradoxical protection mechanism could reflect compensatory changes rather than direct GCH1 function
  13. 2018 Medium

    Validating miRNA-mediated GCH1 regulation in vivo: miR-206 directly targets the GCH1 3′-UTR to reduce BH4/NO and promote atrial autonomic remodeling; the phenylalanine–GFRP axis was independently confirmed as a pharmacological activator of GCH1-dependent BH4 synthesis in hypertension.

    Evidence Luciferase reporter and lentiviral overexpression in canine model (miR-206); l-phenylalanine in spontaneously hypertensive rats (GFRP)

    PMID:29436714 PMID:29963647

    Open questions at the time
    • Endogenous miR-206 levels in human cardiac tissue not characterized
    • GFRP structural interaction with GCH1 not resolved at atomic level in this study
  14. 2019 Medium

    Demonstrating GCH1 as a mediator of neuronal apoptosis via iNOS/NO: miR-124 directly suppresses GCH1, and GCH1 knockdown reduces BH4/iNOS activity and LPS-induced spinal neuronal apoptosis after spinal cord injury.

    Evidence Luciferase reporter, intrathecal agomir-124 in rat SCI model, GCH1 KD/OE with BH4, nitrite, and apoptosis readouts

    PMID:31210282

    Open questions at the time
    • Whether GCH1 promotes apoptosis via NO-dependent peroxynitrite or other mechanism unclear
    • Single lab; limited to acute injury context
  15. 2021 High

    Establishing that GCH1/BH4 deficiency impairs tyrosine hydroxylase protein stability and triggers neuroinflammation rather than dopaminergic cell death: zebrafish gch1 CRISPR knockouts lost Th protein but retained dopaminergic neurons, with marked microglial activation.

    Evidence CRISPR/Cas9 zebrafish gch1 knockout with RNAseq, Th immunofluorescence, microglial markers, and behavioral assays

    PMID:34876467

    Open questions at the time
    • Mechanism of Th protein destabilization by BH4 depletion not defined
    • Whether neuroinflammation is cause or consequence of monoamine deficiency not resolved
  16. 2021 Medium

    Uncovering an immunomodulatory function in cancer: GCH1 overexpression in TNBC reprograms tryptophan metabolism to accumulate 5-HTP, which activates AhR to transcribe IDO1, increasing kynurenine and Treg infiltration; GCH1 inhibition enhanced PD-1 blockade efficacy.

    Evidence Metabolomics, AhR ChIP at IDO1 promoter, GCH1 KD/OE, DAHP inhibitor, in vivo xenograft with anti-PD-1

    PMID:34281987

    Open questions at the time
    • 5-HTP–AhR binding affinity not directly measured
    • Applicability beyond TNBC not tested
  17. 2022 Medium

    Defining GCH1/BH4 as a ferroptosis defence axis: GCH1 knockdown sensitized colorectal cancer cells to erastin-induced ferroptosis via enhanced lipid peroxidation and ferritinophagy, while BH4 supplementation fully rescued; EGFR/KRAS signalling was identified as an upstream driver of GCH1 expression.

    Evidence GCH1 siRNA with lipid peroxidation/iron/autophagy assays in CRC cells; phenotypic screen identifying EGFR/KRAS–GCH1 axis in DRG neurons and lung cancer

    PMID:35223839 PMID:36044597

    Open questions at the time
    • Direct BH4 radical-trapping mechanism versus enzymatic antioxidant pathway not distinguished
    • EGFR-to-GCH1 transcriptional intermediates not fully mapped
  18. 2022 Medium

    Identifying additional transcriptional regulators: PRRX2 and METTL3-stabilized PBX1 were each validated by ChIP as direct transcriptional activators of GCH1 in glioblastoma and gastric cancer, respectively, linking GCH1/BH4 to ferroptosis resistance and tumour proliferation.

    Evidence ChIP and dual-luciferase assays for PRRX2 and PBX1 at GCH1 promoter; Me-RIP-seq for METTL3–PBX1; xenograft models

    PMID:35261206 PMID:36266731

    Open questions at the time
    • Whether PRRX2 and PBX1 cooperate or act in distinct tumour contexts unknown
    • Endogenous genomic occupancy not validated genome-wide
  19. 2023 Medium

    Revealing post-translational stabilization of GCH1 protein: circSEPT9 blocks GCH1 ubiquitination to increase protein levels and suppress ferroptosis in TNBC, adding ubiquitin-proteasomal regulation to the GCH1 control repertoire.

    Evidence RNA immunoprecipitation, RNA pull-down, ubiquitination assay, ferroptosis readouts in TNBC cells

    PMID:38040194

    Open questions at the time
    • The E3 ubiquitin ligase targeting GCH1 is not identified
    • Whether circSEPT9 directly shields GCH1 from the ligase or acts indirectly is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of BH4-mediated NRF2 activation, the identity of the E3 ligase(s) controlling GCH1 ubiquitination, the mechanism by which BH4 depletion destabilizes tyrosine hydroxylase protein, and whether the ferroptosis-suppressive function of BH4 operates via direct radical trapping or enzymatic lipid repair.
  • No structural model of how BH4 activates NRF2 signalling
  • E3 ligase for GCH1 ubiquitination unidentified
  • Direct radical-trapping capacity of BH4 versus enzymatic mechanism in ferroptosis not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 3 GO:0016491 oxidoreductase activity 3
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-8953854 Metabolism of RNA 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2
Partners
AHRAUF1GFRPHURNRF2PBX1PRRX2
Complex memberships
GCH1-GFRP feedback regulatory complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Conditional deletion of Gch1 in macrophages (Gch1fl/fl Tie2cre) abolishes de novo BH4 biosynthesis and eliminates iNOS-dependent NO production (as measured by L-citrulline production, EPR spin trapping, and nitrite accumulation), demonstrating that GCH1-derived BH4 is an obligate cofactor for iNOS NO synthesis. BH4 deficiency also causes iNOS-driven superoxide production and selectively impairs NRF2-dependent antioxidant gene induction (gclm, prdx1, gsta3, nqo1, catalase) after inflammatory activation. Conditional knockout mouse (Gch1fl/fl Tie2cre), L-citrulline assay, EPR spin trapping, nitrite accumulation, dihydroethidium ROS assay, gene expression analysis, sepiapterin rescue Free radical biology & medicine High 25451639
2014 Genetic ablation of Gch1 (global knockout via Sox2cre) causes embryonic lethality by E13.5 associated with bradycardia at E11.5. Maternal BH4 supplementation maintains embryo BH4 until E11.5 via placental transfer but cannot rescue lethality alone; partial rescue to E15.5 requires combined BH4 and L-DOPA supplementation, placing GCH1-derived BH4 as essential for embryonic cardiac function and survival. Conditional/global Gch1 knockout mouse (Sox2cre), embryo BH4 measurement, unbiased metabolomics, maternal supplementation rescue experiment, cardiac monitoring Developmental biology High 25557619
2018 Loss of Gch1 in both endothelial cells and leucocytes (Gch1fl/fl Tie2cre × ApoE−/−) increases atherosclerosis burden, plaque macrophage content, aortic VCAM-1 expression, and foam cell formation, while reducing endothelium-dependent vasodilation. Bone marrow chimera experiments demonstrated that loss of Gch1 in both endothelial cells AND leucocytes is required to accelerate atherosclerosis, implicating GCH1/BH4 in eNOS coupling and macrophage redox signalling during atherogenesis. Conditional knockout mouse, ApoE−/− hyperlipidaemic model, aortic chemiluminescence, VCAM-1 expression, bone marrow chimeras, ex vivo vasodilation Cardiovascular research High 29596571
2012 BH4-deficient hph-1 mice (reduced Gch1 expression and GTPCH enzymatic activity) display increased resting heart rate attributable to enhanced β-adrenergic sensitivity, not impaired vagal function. Propranolol normalises tachycardia; stellate ganglion stimulation and isoproterenol (but not forskolin) elicit greater tachycardia in hph-1 mice alongside elevated β1-adrenoceptor protein and amplified cAMP response, identifying GCH1/BH4 as a regulator of cardiac β-adrenergic signalling. hph-1 BH4-deficient mouse model, in vivo autonomic pharmacology, vagal nerve stimulation, stellate ganglion stimulation, isoproterenol/forskolin in vitro assays, β1-adrenoceptor western blot, cAMP assay Cardiovascular research High 22241166
2007 A common GCH1 variant C+243T in the 3′-UTR decreases reporter gene expression in transfected plasmid assays, predicts renal NO and neopterin excretion, and associates with autonomic traits (baroreceptor coupling, pulse interval) and blood pressure in a twin study, establishing that GCH1 3′-UTR variation functionally reduces GCH1 expression and thereby modulates NO production and cardiovascular autonomic activity. Twin study, 3′-UTR reporter assay in transfected cells, renal NO/neopterin excretion measurement, heritability analysis The Journal of clinical investigation Medium 17717598
2008 A GCH1 haplotype (X haplotype: rs8007267A, rs3783641T, rs10483639G) is associated with significantly lower vascular GCH1 mRNA expression and reduced plasma and vascular BH4 levels in coronary artery disease patients, resulting in increased eNOS-derived superoxide (L-NAME-inhibitable), reduced endothelium-dependent vasorelaxation to acetylcholine. This establishes GCH1 genetic variation as a determinant of eNOS coupling state in human vascular disease. Human vascular tissue (internal mammary artery, saphenous vein from 347 CAD patients), lucigenin-enhanced chemiluminescence for superoxide, ex vivo vasodilation, GCH1 mRNA quantification, plasma/vascular BH4 measurement, haplotype analysis Journal of the American College of Cardiology High 18598896
2018 Leukocyte-specific BH4 deficiency (Gch1fl/fl Tie2cre) results in enhanced intracellular control of Mycobacterium tuberculosis infection relative to wild-type mice, whereas Nos2−/− mice are susceptible. Gene expression analysis of Gch1-deficient macrophages reveals alterations in inflammatory response, lysosomal function, cell survival, and cellular metabolism, demonstrating NO-independent antimycobacterial functions of Gch1. Gch1fl/fl Tie2cre conditional KO, Nos2−/− comparison, in vitro and in vivo M. tuberculosis infection, RNAseq gene expression, murine and human leukocytes Nature communications High 30573728
2021 Loss-of-function zebrafish gch1 mutants (CRISPR/Cas9) develop monoaminergic neurotransmitter deficiencies by 5 dpf and markedly reduced tyrosine hydroxylase (Th) protein without loss of dopaminergic neurons, followed by movement deficits and lethality. RNAseq identified highly upregulated innate immune transcripts and microglial activation in gch1−/− brains, demonstrating that GCH1/BH4 deficiency impairs Th protein homeostasis and triggers neuroinflammation rather than primary dopaminergic cell death. CRISPR/Cas9 zebrafish knockout, RNAseq, immunofluorescence for Th and microglial markers, behavioral assays, L-DOPA rescue The Journal of neuroscience High 34876467
2004 In-vivo yeast complementation assays (Saccharomyces cerevisiae fol2 deletion) of GCH1 missense and frameshift mutations showed that ΔG693 and V205G abolish enzymatic function of GTP cyclohydrolase I, while P199A causes a conditional defect, providing direct functional validation of pathogenic GCH1 mutations. Yeast complementation assay (S. cerevisiae fol2 strain), GCH1 enzymatic function assessment in vivo Journal of inherited metabolic disease Medium 15303002
2017 GCH1 is transcriptionally regulated by NRF2 (NF-E2-related factor 2). Overexpression of GCH1 restores BH4 levels and NO production after irradiation, reducing ROS and protecting skin cells and rat skin from radiation-induced injury. GCH1 knockdown abolishes NRF2-mediated radioprotection, placing GCH1 as a key downstream effector in the NRF2/GCH1/BH4 antioxidant axis. GCH1 overexpression/knockdown in skin cells, rat irradiation model, BH4 measurement, NO measurement, ROS assay, NRF2 reporter/ChIP-like analysis The Journal of investigative dermatology Medium 28596000
2016 Nicotine inhibits HuR (human antigen R) translocation from nucleus to cytoplasm, reducing HuR binding to AU-rich elements in the GCH1 3′-UTR, thereby destabilising GCH1 mRNA and reducing GTPCH1 protein, BH4, and NO production in endothelial cells. GCH1 overexpression or BH4 supplementation rescues nicotine-induced endothelial dysfunction and atherosclerosis in ApoE−/− mice. HuR-GCH1 mRNA binding assay, GTPCH1 3′-UTR stability analysis, siRNA, GCH1 overexpression, ApoE−/− mouse model, NO/ROS measurement Journal of cellular and molecular medicine Medium 30091833
2016 Liraglutide (GLP-1 analogue) upregulates GTPCH1 and eNOS via a PI3K/Akt–Foxo1 pathway in endothelial cells; pharmacological blockade of PI3K (LY294002), Foxo1 nuclear export (TFP), GTPCH1 (DAHP), or NOS (L-NAME) each abolishes liraglutide-restored angiogenesis, establishing GCH1 as a downstream effector of the PI3K/Akt–Foxo1 axis in endothelial NO-dependent angiogenesis. Pathway inhibitor dissection, GTPCH1/eNOS western blot, endothelial tube formation assay, PI3K/Akt/Foxo1 phosphorylation analysis Peptides Medium 27777063
2016 Metformin recouples eNOS in fluctuating-glucose-impaired endothelial cells by upregulating GTPCH1 and BH4 via an AMPK-dependent pathway; AMPK inhibitor compound C abolishes the effect, while NADPH oxidase inhibition is a parallel mechanism, placing GCH1 downstream of AMPK in eNOS coupling. AMPK inhibitor (compound C), L-NAME, apocynin, GTPCH1/BH4 measurement, ROS/NO assay in HUVECs Journal of diabetes and its complications Medium 27217019
2018 GCH1 is validated as a direct target of miR-206 by luciferase assay in myocardial cells; miR-206 overexpression in canine pulmonary vein fat pad reduces GCH1 expression ~60%, decreases BH4 and NO content, and exacerbates atrial autonomic nerve remodeling and atrial effective refractory period, while GCH1 overexpression reverses these effects. Luciferase reporter assay (miR-206 binding to GCH1 3′-UTR), lentiviral overexpression in vivo (canine), BH4/NO measurement, PGP9.5 immunostaining Pacing and clinical electrophysiology Medium 29436714
2018 l-Phenylalanine administration in spontaneously hypertensive rats restores vascular BH4 levels and NO-dependent vasodilation by activating the GCH1–GFRP (GCH1 feedback regulatory protein) complex, demonstrating that this protein complex is a pharmacologically accessible regulatory node for endothelial BH4 synthesis. Rodent model of hypertension, vascular function assays, BH4 measurement, l-phenylalanine pharmacology JACC. Basic to translational science Medium 29963647
2022 GCH1/BH4 acts as a ferroptosis defence mechanism: GCH1 knockdown in colorectal cancer cells decreases BH4, enhances erastin-induced lipid peroxidation and ferrous iron accumulation, and activates ferritinophagy specifically during erastin (but not RSL3) treatment. BH4 supplementation fully rescues ferroptotic features, and autophagy inhibition reverses the sensitisation of GCH1-knockdown cells to erastin, establishing that GCH1/BH4 suppresses ferroptosis partly via ferritinophagy suppression. GCH1 siRNA/pharmacological inhibition, lipid peroxidation assay, ferrous iron measurement, autophagy inhibitor (ferritinophagy), BH4 supplementation rescue, in vivo xenograft Frontiers in cell and developmental biology Medium 35223839
2022 EGFR/KRAS signalling drives Gch1 expression in injured dorsal root ganglion neurons; pharmacological EGFR inhibition suppresses GCH1 and BH4 and reduces neuropathic pain in rodents. A phenotypic screen of ~1000 compounds identified EGFR/KRAS as upstream regulators of Gch1 transcription, and GCH1/BH4 was found to act downstream of KRAS to promote lung cancer cell growth. Phenotypic drug screen (~1000 compounds), rodent DRG injury model, GCH1/BH4 measurement, EGFR inhibitor treatment, pain behavioural assays, lung cancer cell assays Science translational medicine Medium 36044597
2021 GCH1 overexpression in triple-negative breast cancer reprograms tryptophan metabolism to accumulate 5-hydroxytryptophan (5-HTP) in the cytoplasm, which activates aryl hydrocarbon receptor (AhR), which then binds the IDO1 promoter to upregulate IDO1 transcription, increasing kynurenine and promoting Treg infiltration. GCH1 inhibitor DAHP reverses IDO1 expression and enhances response to PD-1 blockade. Metabolomics, AhR ChIP (IDO1 promoter), GCH1 KD/OE, in vivo xenograft, DAHP inhibitor, flow cytometry for Tregs/PD-1 Journal for immunotherapy of cancer Medium 34281987
2019 miR-124 directly binds the GCH1 mRNA 3′-UTR (validated by luciferase reporter assay and TargetScan), suppressing GCH1 expression after spinal cord injury. GCH1 knockdown reduces BH4, nitrite, and iNOS activity and decreases LPS-induced spinal neuronal apoptosis, while GCH1 overexpression reverses miR-124-mediated apoptosis suppression, establishing GCH1 as a pro-apoptotic mediator via the BH4/iNOS/NO axis in spinal neurons. Luciferase reporter assay, intrathecal agomir-124 injection in rat SCI model, GCH1 KD/OE, HPLC for BH4, Griess reagent for nitrite, iNOS activity assay, flow cytometry for apoptosis European review for medical and pharmacological sciences Medium 31210282
2022 PRRX2 functions as a transcription factor that directly upregulates GCH1 expression in glioblastoma stem cells; circLRFN5 promotes PRRX2 ubiquitin-proteasomal degradation to reduce GCH1/BH4 and induce ferroptosis. Dual-luciferase reporter and ChIP assays confirmed PRRX2 binding to the GCH1 promoter. ChIP assay, dual-luciferase reporter (PRRX2 at GCH1 promoter), RNA pull-down, RNA immunoprecipitation, ubiquitination assay, ferroptosis assays (BODIPY, GSH, MDA), xenograft Journal of experimental & clinical cancer research Medium 36266731
2022 METTL3-mediated m6A modification stabilises PBX1 mRNA; PBX1 protein acts as a transcription factor that induces GCH1 expression (validated by ChIP and luciferase assays), leading to elevated BH4 levels that promote gastric cancer proliferation and metastasis. Me-RIP sequencing, ChIP (PBX1 at GCH1 promoter), western blot, xenograft, LC-MS for BH4, METTL3 KD Cancer communications Medium 35261206
2016 AUF1 RNA-binding protein binds an AU-rich element in the GCH1 3′-UTR (validated by luciferase assay), stabilising GCH1 mRNA. AUF1 knockdown reduces GCH1 expression and suppresses esophageal squamous cell carcinoma cell proliferation, establishing AUF1 as a post-transcriptional regulator of GCH1. Luciferase reporter assay (GCH1 3′-UTR ARE), siRNA KD, microarray, colony formation assay International journal of oncology Medium 27826622
2023 GCH1 knockdown in LPS-stimulated macrophages increases ferroptosis markers (ROS, MDA; decreased GSH/GPX4), promotes M1 polarisation (increased iNOS, IL-6, TNF-α, IL-1β), and suppresses AMPK pathway activity, demonstrating that GCH1 suppresses LPS-induced ferroptosis in macrophages via AMPK signalling. GCH1 siRNA in Raw264.7 cells, ROS/SOD/MDA/GSH assays, western blot (GPX4, ACSL4, AMPK, p-AMPK), immunofluorescence Inflammation research Low 37735250
2023 SRSF1 binds to and upregulates circSEPT9 (validated by RNA immunoprecipitation and RNA pull-down); circSEPT9 blocks ubiquitination of GCH1 protein, increasing GCH1 protein levels and suppressing ferroptosis in TNBC cells, establishing a SRSF1–circSEPT9–GCH1 post-translational axis. RNA immunoprecipitation, RNA pull-down, ubiquitination assay, western blot, ferric ion/ROS/MDA/GSH assays Journal of proteomics Medium 38040194
1997 Two splice-site mutations in GCH1 (A→G at intron 1 position −2 causing exon 2 skipping; A→G at intron 2 position −2 creating a new splice acceptor one bp upstream) generate frameshifted, truncated GTP cyclohydrolase I polypeptides, demonstrating loss-of-function as the molecular mechanism for dopa-responsive dystonia. RT-PCR, direct sequencing of patient GCH1 mRNA, splice-site mutation analysis Neurogenetics Medium 10732814

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis. Frontiers in cell and developmental biology 163 35223839
2009 Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. Journal of neurology, neurosurgery, and psychiatry 129 19332422
2022 SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1. Cell death and differentiation 128 36443440
2022 CircLRFN5 inhibits the progression of glioblastoma via PRRX2/GCH1 mediated ferroptosis. Journal of experimental & clinical cancer research : CR 126 36266731
2014 Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation. Free radical biology & medicine 117 25451639
2017 The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade. The Journal of investigative dermatology 81 28596000
2008 Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain. Pain 79 19081190
2007 Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk. The Journal of clinical investigation 73 17717598
2008 GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. Journal of the American College of Cardiology 70 18598896
2014 Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain. Pain 65 25218601
2011 GCH1, BH4 and pain. Current pharmaceutical biotechnology 63 21466440
1998 High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Annals of neurology 59 9585358
2007 Lack of influence of GTP cyclohydrolase gene (GCH1) variations on pain sensitivity in humans. Molecular pain 57 17343757
2022 m6 A-mediated regulation of PBX1-GCH1 axis promotes gastric cancer proliferation and metastasis by elevating tetrahydrobiopterin levels. Cancer communications (London, England) 52 35261206
2007 Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5. Neurology 49 17804835
2021 GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer. Journal for immunotherapy of cancer 48 34281987
2016 Metformin attenuates fluctuating glucose-induced endothelial dysfunction through enhancing GTPCH1-mediated eNOS recoupling and inhibiting NADPH oxidase. Journal of diabetes and its complications 47 27217019
2000 Dopa-responsive dystonia: mutation analysis of GCH1 and analysis of therapeutic doses of L-dopa. German Dystonia Study Group. Neurology 46 11113234
2005 (G-H)*-C and G-(C-H)* radicals derived from the guanine.cytosine base pair cause DNA subunit lesions. Proceedings of the National Academy of Sciences of the United States of America 45 15814617
2002 Neuropathology of a case of dopa-responsive dystonia associated with a new genetic locus, DYT14. Neurology 45 12084887
2018 Nicotine induces endothelial dysfunction and promotes atherosclerosis via GTPCH1. Journal of cellular and molecular medicine 44 30091833
2014 A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. American journal of hematology 43 24136375
2007 Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms. Clinical chemistry 43 17363416
2018 Roles for endothelial cell and macrophage Gch1 and tetrahydrobiopterin in atherosclerosis progression. Cardiovascular research 41 29596571
2024 Inhibition of Ferroptosis by Mesenchymal Stem Cell-Derived Exosomes in Acute Spinal Cord Injury: Role of Nrf2/GCH1/BH4 Axis. Neurospine 38 38955534
2022 Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer. Science translational medicine 38 36044597
2009 Autosomal dominant GTP cyclohydrolase I (AD GCH 1) deficiency (Segawa disease, dystonia 5; DYT 5). Chang Gung medical journal 35 19292934
2014 A requirement for Gch1 and tetrahydrobiopterin in embryonic development. Developmental biology 34 25557619
2007 Frequency of GCH1 deletions in Dopa-responsive dystonia. Journal of neurology, neurosurgery, and psychiatry 34 17898029
2018 Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin. Nature communications 33 30573728
2020 GCH1 variants contribute to the risk and earlier age-at-onset of Parkinson's disease: a two-cohort case-control study. Translational neurodegeneration 31 32746945
2016 Upregulation of AUF1 is involved in the proliferation of esophageal squamous cell carcinoma through GCH1. International journal of oncology 30 27826622
2015 Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease. Parkinsonism & related disorders 30 25634433
2019 Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression. Pharmaceuticals (Basel, Switzerland) 29 30625990
2023 GCH1 reduces LPS-induced alveolar macrophage polarization and inflammation by inhibition of ferroptosis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 28 37735250
2012 Design of a single AAV vector for coexpression of TH and GCH1 to establish continuous DOPA synthesis in a rat model of Parkinson's disease. Molecular therapy : the journal of the American Society of Gene Therapy 27 22294150
1999 GCH1 mutation in a patient with adult-onset oromandibular dystonia. Neurology 27 10078749
2019 Liraglutide ameliorates palmitate-induced oxidative injury in islet microvascular endothelial cells through GLP-1 receptor/PKA and GTPCH1/eNOS signaling pathways. Peptides 26 31770577
2018 Common and rare GCH1 variants are associated with Parkinson's disease. Neurobiology of aging 26 30314816
2023 SRSF1 inhibits ferroptosis and reduces cisplatin chemosensitivity of triple-negative breast cancer cells through the circSEPT9/GCH1 axis. Journal of proteomics 25 38040194
2002 Mutations of GCH1 in Dopa-responsive dystonia. Journal of neural transmission (Vienna, Austria : 1996) 25 11956954
2022 Novel Immune-Related Ferroptosis Signature in Esophageal Cancer: An Informatics Exploration of Biological Processes Related to the TMEM161B-AS1/hsa-miR-27a-3p/GCH1 Regulatory Network. Frontiers in genetics 24 35281840
2012 GCH1-polymorphism and pain sensitivity among women with provoked vestibulodynia. Molecular pain 24 22971341
2008 Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk. Mutation research 24 18515178
2016 Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway. Peptides 23 27777063
2021 GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 34876467
2018 l-Phenylalanine Restores Vascular Function in Spontaneously Hypertensive Rats Through Activation of the GCH1-GFRP Complex. JACC. Basic to translational science 22 29963647
2014 GCH1 variants, tetrahydrobiopterin and their effects on pain sensitivity. Scandinavian journal of pain 22 29913682
2004 GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations. Journal of inherited metabolic disease 22 15303002
2002 Phenocopies in a large GCH1 mutation positive family with dopa responsive dystonia: confusing the picture? Journal of neurology, neurosurgery, and psychiatry 21 12023430
2017 GCH1 plays a role in the high-altitude adaptation of Tibetans. Zoological research 20 28585439
2013 KCNS1, but not GCH1, is associated with pain intensity in a black southern African population with HIV-associated sensory neuropathy: a genetic association study. Journal of acquired immune deficiency syndromes (1999) 20 23314412
2010 Four novel mutations in the GCH1 gene of Chinese patients with dopa-responsive dystonia. Movement disorders : official journal of the Movement Disorder Society 20 20437540
2023 GTP cyclohydroxylase1 (GCH1): Role in neurodegenerative diseases. Gene 19 37652170
2010 GCH1 mutation and clinical study of Chinese patients with dopa-responsive dystonia. Movement disorders : official journal of the Movement Disorder Society 19 20108370
2006 Utility of MLPA in deletion analysis of GCH1 in dopa-responsive dystonia. Neurogenetics 19 17111153
2000 Propachlor removal by Pseudomonas strain GCH1 in an immobilized-cell system. Applied and environmental microbiology 19 10698790
2018 Genetic variants of GCH1 associate with chronic and acute crisis pain in African Americans with sickle cell disease. Experimental hematology 18 30031848
2017 Generation of an iPSC line from a patient with GTP cyclohydrolase 1 (GCH1) deficiency: HDMC0061i-GCH1. Stem cell research 16 28395739
2011 Dopa-responsive dystonia with a novel initiation codon mutation in the GCH1 gene misdiagnosed as cerebral palsy. Journal of Korean medical science 16 21935284
2012 Regulation of β-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin. Cardiovascular research 15 22241166
2010 High frequency of multiexonic deletion of the GCH1 gene in a Taiwanese cohort of dopa-response dystonia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 15 20082337
2008 Molecular analyses of GCH-1, TH and parkin genes in Chinese dopa-responsive dystonia families. Clinical genetics 15 18554280
2024 CTRP13 attenuates atherosclerosis by inhibiting endothelial cell ferroptosis via activating GCH1. International immunopharmacology 14 39541845
2012 Analysis of a previously identified "pain-protective" haplotype and individual polymorphisms in the GCH1 gene in Africans with HIV-associated sensory neuropathy: a genetic association study. Journal of acquired immune deficiency syndromes (1999) 14 22293547
2010 Different SNP combinations in the GCH1 gene and use of labor analgesia. Molecular pain 14 20633294
2023 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. Journal of neural transmission (Vienna, Austria : 1996) 13 37638996
2021 GCH1-regulated miRNAs are potential targets for microglial activation in neuropathic pain. Bioscience reports 13 34402860
2017 GCH1 mutations are common in Serbian patients with dystonia-parkinsonism: Challenging previously reported prevalence rates of DOPA-responsive dystonia. Parkinsonism & related disorders 13 28958832
2004 Wide expressivity variation and high but no gender-related penetrance in two dopa-responsive dystonia families with a novel GCH-I mutation. Movement disorders : official journal of the Movement Disorder Society 13 15390021
1997 Two previously unrecognized splicing mutations of GCH1 in Dopa-responsive dystonia: exon skipping and one base insertion. Neurogenetics 13 10732814
2018 GCH1 attenuates cardiac autonomic nervous remodeling in canines with atrial-tachypacing via tetrahydrobiopterin pathway regulated by microRNA-206. Pacing and clinical electrophysiology : PACE 12 29436714
2022 Lonicerae japonicae flos ameliorates radiotherapy-induced mesenteric artery endothelial dysfunction through GTPCH1/BH4/eNOS pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 11 35594639
2022 Naringenin upregulates GTPCH1/eNOS to ameliorate high glucose-induced retinal endothelial cell injury. Experimental and therapeutic medicine 11 35607381
2021 Ligustilide Prevents Radiation Enteritis by Targeting Gch1/BH4/eNOS to Improve Intestinal Ischemia. Frontiers in pharmacology 11 33967762
2016 Aging modifies the effect of GCH1 RS11158026 on DAT uptake and Parkinson's disease clinical severity. Neurobiology of aging 11 27871051
2006 Developmental regulation of GTP-CH1 in the porcine lung and its relationship to pulmonary vascular relaxation. Pediatric research 11 16641207
2003 Behavioral correction of Parkinsonian rats following the transplantation of immortalized fibroblasts genetically modified with TH and GCH genes. Parkinsonism & related disorders 11 12915073
1981 Lack of effective messenger RNA for beta 2-microglobulin in a gestational human choriocarcinoma cell line (GCH-1). Cancer research 11 6167351
2020 Autosomal dominant GCH1 mutations causing spastic paraplegia at disease onset. Parkinsonism & related disorders 10 32278297
2019 A Compound Heterozygote for GCH1 Mutation Represents a Case of Atypical Dopa-Responsive Dystonia. Journal of molecular neuroscience : MN 10 30911941
2019 MiR-124 inhibits spinal neuronal apoptosis through binding to GCH1. European review for medical and pharmacological sciences 10 31210282
2018 Regulation of cortical and peripheral GCH1 expression and biopterin levels in schizophrenia-spectrum disorders. Psychiatry research 10 29471261
2018 Study of GCH1 and TH genes in Chinese patients with Parkinson's disease. Neurobiology of aging 10 29724574
2017 Dopa-responsive dystonia in Chinese patients: Including a novel heterozygous mutation in the GCH1 gene with an intermediate phenotype and one case of prenatal diagnosis. Neuroscience letters 10 28087438
2021 GCH1 mutations in hereditary spastic paraplegia. Clinical genetics 9 33713342
2018 Interferon- Gamma- Inducible Guanosine Triphosphate Cyclohydrolase 1 (GTP-CH1) Pathway Is Associated with Frailty in Egyptian Elderly. Reports of biochemistry & molecular biology 9 30324118
2013 Novel GCH-1 mutations and unusual long-lasting dyskinesias in Korean families with dopa-responsive dystonia. Parkinsonism & related disorders 9 24018121
2009 Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain). Journal of neurology 9 19533203
2023 Suppression of GCH1 Sensitizes Ovarian Cancer and Breast Cancer to PARP Inhibitor. Journal of oncology 7 36793373
2016 Low frequency of GCH1 and TH mutations in Parkinson's disease. Parkinsonism & related disorders 7 27185167
2012 A GCH1 haplotype and risk of neural tube defects in the National Birth Defects Prevention Study. Molecular genetics and metabolism 7 23059057
2005 A case of late-onset Segawa syndrome (autosomal dominant dopa-responsive dystonia) with a novel mutation of the GTP-cyclohydrase I (GCH1) gene. Clinical neurology and neurosurgery 7 16289769
2022 Splicing factor SF3B3, a NS5-binding protein, restricts ZIKV infection by targeting GCH1. Virologica Sinica 6 36572150
2017 Variability of presynaptic nigrostriatal dopaminergic function and clinical heterogeneity in a dopa-responsive dystonia family with GCH-1 gene mutation. Journal of neurology 6 29290055
2014 Genetics and pathophysiology of primary dystonia with special emphasis on DYT1 and DYT5. Seminars in neurology 6 25192508
2012 Occurrence of GCH1 gene mutations in a group of Indian dystonia patients. Journal of neural transmission (Vienna, Austria : 1996) 6 22373569
2011 A novel missense mutation in GTP cyclohydrolase I (GCH1) gene causes Dopa-responsive dystonia in Chinese Han population. European journal of neurology 6 20491893
2006 [Clinical analysis of dopa-responsive dystonia and mutation analysis of the GCH I gene]. Zhonghua er ke za zhi = Chinese journal of pediatrics 6 17044972
2006 Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene associated with DYT5 dystonia. Archives of neurology 6 17101830