Affinage

GCH1

GTP cyclohydrolase 1 · UniProt P30793

Length
250 aa
Mass
27.9 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCH1 encodes GTP cyclohydrolase 1, the rate-limiting enzyme of de novo tetrahydrobiopterin (BH4) synthesis whose activity is indispensable for nitric oxide synthase and aromatic amino acid hydroxylase function across vascular, immune, and neuronal compartments (PMID:25451639, PMID:15303002). In macrophages, GCH1-derived BH4 is required for iNOS to produce NO rather than uncoupled superoxide, and BH4-dependent NO generation is in turn required for NRF2-dependent antioxidant gene induction during inflammatory activation (PMID:25451639); in endothelial cells GCH1/BH4 maintains eNOS coupling, and combined endothelial/leukocyte loss accelerates atherosclerosis and impairs endothelium-dependent vasodilation (PMID:29596571). BH4 deficiency reveals NO-independent roles of GCH1 in macrophage lysosomal function, survival, and metabolism that shape anti-mycobacterial immunity (PMID:30573728), and a defense role against ferroptosis in which GCH1/BH4 limits lipid peroxidation and ferritinophagy (PMID:35223839). Genetically, GCH1 is indispensable for embryonic development, with global ablation causing BH4-dependent embryonic lethality and bradycardia that requires both BH4 and downstream catecholamine synthesis for partial rescue (PMID:25557619), and BH4 deficiency disrupts tyrosine hydroxylase homeostasis and monoaminergic neurotransmission while activating innate immune and microglial responses rather than causing dopaminergic cell death (PMID:34876467). GCH1/BH4 further tunes cardiac sympathetic/β-adrenergic tone (PMID:22241166) and supports tumor growth through BH4-dependent and metabolic-reprogramming mechanisms, including 5-HTP/AhR-driven IDO1 induction and immunosuppression (PMID:34281987). Loss-of-function GCH1 mutations—missense, nonsense, frameshift, and splice-site alleles that abolish or reduce enzymatic activity—cause dopa-responsive dystonia / hyperphenylalaninemia (PMID:15303002, PMID:10732814, PMID:16289769). GCH1 is controlled at multiple levels: transcriptionally by Nrf2 and a METTL3–PBX1 axis (PMID:28596000, PMID:35261206), post-transcriptionally through 3'UTR AU-rich elements bound by stabilizing factors HuR and AUF1 and repressing microRNAs miR-124 and miR-206 (PMID:30091833, PMID:27826622, PMID:31210282, PMID:29436714), and allosterically through the GCH1–GFRP complex, which is activated by phenylalanine to elevate vascular BH4 (PMID:29963647).

Mechanistic history

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

    Established that splice-site mutations are a molecular mechanism of GCH1 loss-of-function in disease by showing they generate aberrant, truncated cyclohydrolase transcripts.

    Evidence RT-PCR and sequencing of patient mRNA characterizing aberrant transcripts in dopa-responsive dystonia

    PMID:10732814

    Open questions at the time
    • Did not measure residual enzymatic activity of truncated products
    • No structural basis for haploinsufficiency
  2. 2004 High

    Directly demonstrated that specific GCH1 missense and frameshift alleles abolish or conditionally impair enzymatic function, distinguishing damaging from tolerated variants.

    Evidence Functional complementation in a fol2-null S. cerevisiae strain with direct enzymatic activity readout

    PMID:15303002

    Open questions at the time
    • Single lab
    • Yeast context may not reflect human GCH1-GFRP regulation
  3. 2005 Low

    Linked GCH1 nonsense mutation to reduced enzyme activity in accessible patient cells, providing a measurable correlate of impaired BH4 synthesis.

    Evidence Enzymatic activity assay in stimulated patient PBMCs and CSF pterin measurement (single patient, W53X)

    PMID:16289769

    Open questions at the time
    • Single-patient enzymatic measurement, not independently confirmed
    • No genotype-phenotype quantification
  4. 2007 Medium

    Showed a common 3'UTR variant functionally lowers GCH1 expression and links GCH1 dosage to human NO output, autonomic traits, and blood pressure.

    Evidence 3'UTR reporter assay plus twin-pair physiological and hemodynamic analysis (C+243T)

    PMID:17717598

    Open questions at the time
    • Reporter assay does not identify the trans-acting factor
    • Association data correlative
  5. 2012 High

    Defined GCH1/BH4 as a regulator of cardiac sympathetic/β-adrenergic tone, showing BH4 deficiency increases β1-adrenoceptor signaling and cAMP responses without affecting vagal function.

    Evidence hph-1 mouse with propranolol, stellate ganglion and vagal stimulation, isoproterenol/forskolin and cAMP assays

    PMID:22241166

    Open questions at the time
    • Mechanism linking BH4 to β1-adrenoceptor upregulation undefined
    • Whether effect is NO-dependent not resolved
  6. 2014 High

    Established that macrophage GCH1 is required for iNOS-derived NO rather than superoxide, and that BH4-dependent NO is itself required for NRF2-driven antioxidant defense during inflammation.

    Evidence Conditional Gch1 knockout macrophages with L-citrulline, EPR, nitrite, superoxide assays, and sepiapterin rescue

    PMID:25451639

    Open questions at the time
    • Molecular link between NO and NRF2 activation not detailed
    • iNOS protein induction unaffected, so coupling is purely cofactor-level
  7. 2014 High

    Demonstrated that GCH1 is indispensable for embryogenesis, with lethality requiring loss of both BH4 and downstream catecholamine synthesis.

    Evidence Sox2cre global Gch1 knockout with metabolomics, cardiac analysis, and maternal BH4/L-DOPA rescue

    PMID:25557619

    Open questions at the time
    • Tissue driving lethality beyond catecholamine deficit unclear
    • Only partial rescue achieved
  8. 2016 Medium

    Identified upstream signaling controlling GCH1/eNOS coupling, placing GCH1 downstream of AMPK and of PI3K/Akt-Foxo1 in endothelial recoupling.

    Evidence Metformin/AMPK (compound C) and liraglutide/PI3K-Foxo1 (LY294002, TFP) inhibitor experiments in HUVECs

    PMID:27217019 PMID:27777063

    Open questions at the time
    • Whether regulation is transcriptional vs post-translational not resolved
    • Single lab per pathway
  9. 2016 Medium

    Defined 3'UTR AU-rich elements as a hub of GCH1 post-transcriptional control by identifying AUF1 as a stabilizing RNA-binding factor coupled to cancer cell proliferation.

    Evidence AUF1 knockdown, 3'UTR luciferase reporter, microarray, and proliferation assays in esophageal carcinoma

    PMID:27826622

    Open questions at the time
    • Relationship to other ARE factors not addressed
    • Single lab
  10. 2017 Medium

    Placed GCH1 as a transcriptional effector of Nrf2-mediated cytoprotection, showing GCH1 restores BH4/NO and limits NOS uncoupling after radiation injury.

    Evidence GCH1 overexpression in skin cells and rat skin with Nrf2 regulation and BH4/NO/ROS readouts

    PMID:28596000

    Open questions at the time
    • Direct Nrf2 binding to GCH1 not mapped
    • Single lab
  11. 2018 High

    Showed combined endothelial and leukocyte GCH1/BH4 loss accelerates atherosclerosis through impaired vasodilation, adhesion molecule upregulation, and macrophage redox dysregulation.

    Evidence Conditional knockout on ApoE-/- background with bone marrow chimeras, vascular tension, and VCAM-1 assays

    PMID:29596571

    Open questions at the time
    • Relative contribution of NO vs antioxidant gene loss not separated
    • Plaque mechanism downstream of redox not detailed
  12. 2018 High

    Distinguished NO-independent functions of GCH1 by showing leukocyte BH4 deficiency enhances control of M. tuberculosis whereas iNOS loss does not, implicating lysosomal, survival, and metabolic programs.

    Evidence Comparison of Gch1fl/fl Tie2cre vs Nos2-/- mice in M.tb infection with macrophage gene expression analysis

    PMID:30573728

    Open questions at the time
    • Specific BH4-dependent NO-independent effector not identified
    • Mechanism of altered lysosomal function unresolved
  13. 2018 Medium

    Expanded the regulatory network with HuR as a nicotine-responsive ARE-binding stabilizer and miR-206 as a direct repressor linking GCH1 to endothelial dysfunction and cardiac autonomic remodeling, and validated GCH1-GFRP as a pharmacologically activatable BH4 regulator.

    Evidence HuR-3'UTR binding and mRNA stability assays, miR-206 luciferase and in vivo canine overexpression, and l-phenylalanine activation of GCH1-GFRP in hypertensive rats

    PMID:29436714 PMID:29963647 PMID:30091833

    Open questions at the time
    • Cross-regulation among ARE factors and miRNAs unmapped
    • Each axis from a single lab
  14. 2019 Medium

    Added miR-124 as a direct GCH1 3'UTR repressor controlling BH4/iNOS-dependent neuronal apoptosis after spinal cord injury.

    Evidence Luciferase reporter, GCH1 knockdown/overexpression, apoptosis flow cytometry, and rat SCI model

    PMID:31210282

    Open questions at the time
    • In vivo relevance of miR-124-GCH1 axis limited
    • Single lab
  15. 2021 High

    Showed in a vertebrate model that GCH1 deficiency impairs tyrosine hydroxylase homeostasis and triggers innate immune/microglial activation rather than dopaminergic neuron death, reframing the neurological phenotype.

    Evidence CRISPR zebrafish gch1-/- with RNAseq, Th immunohistochemistry, L-DOPA rescue, and microglial assays

    PMID:34876467

    Open questions at the time
    • Mechanism linking BH4 loss to immune activation undefined
    • Motor phenotype not rescued by L-DOPA
  16. 2021 Medium

    Revealed a tumor-promoting GCH1 function through tryptophan metabolic reprogramming, with 5-HTP-driven AhR activation inducing IDO1 and immunosuppression.

    Evidence Metabolomics, AhR ChIP at IDO1 promoter, GCH1 perturbation, and in vivo tumor/immune profiling in TNBC

    PMID:34281987

    Open questions at the time
    • How GCH1/BH4 drives 5-HTP accumulation mechanistically not fully resolved
    • Single lab
  17. 2022 Medium

    Connected oncogenic signaling and transcription to GCH1 induction, defining EGFR/KRAS upstream control in pain and lung cancer and a METTL3-PBX1 axis driving GCH1 in gastric cancer.

    Evidence Phenotypic compound screen with EGFR/KRAS inhibitors in DRG neurons, and Me-RIP/PBX1 ChIP with knockdowns in gastric cancer

    PMID:35261206 PMID:36044597

    Open questions at the time
    • Whether EGFR/KRAS act via PBX1 or independently unclear
    • Each axis from a single lab
  18. 2022 Medium

    Established GCH1/BH4 as a ferroptosis defense system, showing GCH1 loss enhances lipid peroxidation and selectively activates ferritinophagy during erastin-induced ferroptosis.

    Evidence GCH1 knockdown/inhibition with BH4 rescue, lipid peroxidation and iron assays, autophagy inhibitors, and xenografts in colorectal cancer

    PMID:35223839

    Open questions at the time
    • Why ferritinophagy is erastin- but not RSL3-specific unexplained
    • Single lab
  19. 2023 Low

    Extended ferroptosis and macrophage links by associating GCH1 with AMPK-dependent ferroptosis/M1 polarization and a circSEPT9-mediated protection of GCH1 from ubiquitin-dependent degradation.

    Evidence GCH1 siRNA with ferroptosis/polarization markers and AMPK Western blot; RNA-IP/pulldown and ubiquitination assays for SRSF1/circSEPT9/GCH1

    PMID:37735250 PMID:38040194

    Open questions at the time
    • AMPK link correlative and mechanistic pathway not directly demonstrated
    • circRNA blocking ubiquitination supported by limited functional data
    • Not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple transcriptional, ARE/miRNA post-transcriptional, allosteric GFRP, and protein-stability inputs are integrated to set GCH1/BH4 levels in a given cell type, and how BH4 exerts its NO-independent effects, remain unresolved.
  • No unified regulatory hierarchy across HuR/AUF1/miR-124/miR-206/Nrf2/PBX1/GFRP
  • NO-independent BH4 effector(s) in immunity and ferroptosis unidentified
  • No structural model of human GCH1-GFRP regulation in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 2 GO:0016829 lyase activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AUF1GFRPHURPBX1SRSF1
Complex memberships
GCH1-GFRP complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Conditional deletion of Gch1 in macrophages (Gch1fl/fl Tie2cre mice) abolishes de novo biopterin biosynthesis and eliminates NO production by iNOS (measured by L-citrulline, EPR spin-trapping, and nitrite accumulation), while iNOS protein induction remains normal. BH4-deficient macrophages show increased superoxide from iNOS uncoupling. BH4 deficiency also specifically impairs NRF2-dependent antioxidant gene induction (gclm, prdx1, gsta3, nqo1, catalase) after iNOS activation, identifying BH4-dependent NO generation as a requirement for NRF2 activation in macrophage inflammatory responses. Conditional Gch1 knockout mouse model, L-citrulline production assay, EPR spin-trapping, nitrite accumulation, dihydroethidium superoxide assay, sepiapterin rescue, gene expression analysis Free radical biology & medicine High 25451639
2014 Global genetic ablation of Gch1 in mice causes embryonic lethality by E13.5, associated with bradycardia at E11.5. Maternal BH4 transfer maintains embryonic BH4 levels until E11.5; after this, Gch1-/- embryos become BH4-deficient. Embryonic lethality was partially rescued (to E15.5) by combined maternal BH4 and L-DOPA supplementation, but not by BH4 alone, demonstrating a developmental requirement for both Gch1 activity and downstream catecholamine synthesis. Sox2cre-mediated global Gch1 knockout, metabolomic screen, cardiac functional analysis at E11.5, maternal supplementation rescue experiments Developmental biology High 25557619
2018 In hyperlipidemic ApoE-/- mice with endothelial/leukocyte-specific Gch1 deficiency (Gch1fl/fl Tie2cre x ApoE-/-), loss of BH4 increased atherosclerosis burden and plaque macrophage content, increased aortic VCAM-1 expression, decreased endothelium-dependent vasodilation, increased foam cell formation, and altered redox signalling in macrophages (decreased antioxidant gene expression, increased ROS). Bone marrow chimera experiments showed that loss of Gch1 in both endothelial cells and leucocytes is required to accelerate atherosclerosis. Conditional knockout mice on ApoE-/- background, high-fat feeding, bone marrow chimeras, lucigenin chemiluminescence, vascular tension assays, VCAM-1 expression Cardiovascular research High 29596571
2021 CRISPR/Cas9-generated zebrafish gch1-/- mutants develop marked monoaminergic neurotransmitter deficiencies by 5 dpf, movement deficits by 8 dpf, and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of dopaminergic neurons. L-DOPA improved survival but not motor phenotype. RNAseq identified highly upregulated innate immune transcripts; microglial activation (morphologic and functional) was demonstrated. These findings establish that GCH1 deficiency impairs Th homeostasis and activates innate immune/microglial mechanisms rather than causing dopaminergic cell death. CRISPR/Cas9 zebrafish knockout, RNAseq, immunohistochemistry for Th, L-DOPA rescue, microglial activation assays The Journal of neuroscience High 34876467
2018 Leukocyte-specific BH4 deficiency (Gch1fl/fl Tie2cre) results in enhanced control of M. tuberculosis infection compared to wild-type mice, whereas Nos2-/- mice are susceptible. Comparing these two NO-deficient models reveals NO-independent mechanisms of anti-mycobacterial immunity involving altered inflammatory response, lysosomal function, cell survival and cellular metabolism in Gch1-deficient macrophages. Conditional Gch1 knockout (Gch1fl/fl Tie2cre) vs Nos2-/- mice, M.tb infection model, gene expression analysis, in vitro macrophage infection assays Nature communications High 30573728
2004 Functional complementation analysis in a Saccharomyces cerevisiae strain lacking the endogenous GTP-CH1 gene (FOL2) showed that GCH1 mutations ΔG693 and V205G abolish enzymatic function, while P199A causes a conditional enzymatic defect, providing direct functional characterization of novel missense and frameshift mutations. Yeast complementation assay in fol2-null S. cerevisiae strain, direct enzymatic activity measurement Journal of inherited metabolic disease High 15303002
2018 Nicotine reduces GCH1/GTPCH1 mRNA and protein levels in endothelial cells. HuR (human antigen R) binds to AU-rich elements in the GTPCH1 3' UTR and stabilizes its mRNA. Nicotine inhibits HuR translocation from nucleus to cytosol, thereby destabilizing GTPCH1 mRNA and reducing BH4 and NO levels while increasing ROS. GTPCH1 overexpression or BH4 supplementation rescues nicotine-induced endothelial dysfunction and atherosclerosis in ApoE-/- mice. HuR-GTPCH1 3'UTR binding assay, mRNA stability assay, GTPCH1 overexpression in vitro and in vivo (ApoE-/- mice), Western blot, NO/ROS measurements Journal of cellular and molecular medicine Medium 30091833
2016 GTPCH1 is upregulated by metformin in endothelial cells through an AMPK-dependent pathway. Metformin recouples eNOS by restoring GTPCH1 and BH4 levels reduced by fluctuating glucose. Addition of compound C (AMPK inhibitor) abolishes the metformin-mediated upregulation of GTPCH1 and BH4, establishing AMPK as an upstream regulator of GTPCH1 in this context. GTPCH1/BH4 measurement in HUVECs, AMPK inhibitor (compound C) experiments, NOS inhibitor and NADPH oxidase inhibitor comparisons, ROS/NO quantification Journal of diabetes and its complications Medium 27217019
2016 Liraglutide restores angiogenesis impaired by palmitate in HUVECs by upregulating GTPCH1 and eNOS levels via a PI3K/Akt-Foxo1-dependent mechanism. PI3K inhibitor LY294002 and Foxo1 nuclear export inhibitor TFP both abolished liraglutide-induced GTPCH1 and eNOS upregulation, placing GTPCH1 downstream of PI3K/Akt-Foxo1 signaling. PI3K/Akt/Foxo1 pathway inhibitor experiments, GTPCH1 inhibitor (DAHP), NOS inhibitor (L-NAME), tube formation assays, Western blot in HUVECs Peptides Medium 27777063
2017 NF-E2-related factor 2 (Nrf2) transcriptionally regulates GCH1 expression. GCH1 overexpression restores BH4 levels and NO production after radiation, decreases radiation-induced ROS, and protects skin cells and rat skin from radiation-induced damage. GCH1 was identified as a key effector of Nrf2-mediated protection by inhibiting NOS uncoupling and ROS amplification. GCH1 overexpression in skin cells and rat model, Nrf2 regulation analysis, BH4/NO/ROS measurement, radiation injury assays The Journal of investigative dermatology Medium 28596000
2012 Reduced Gch1 expression and BH4 deficiency in hph-1 mice causes tachycardia through enhanced β-adrenergic sensitivity. Propranolol normalized resting tachycardia; stellate ganglion stimulation and isoproterenol (but not forskolin) induced greater tachycardia in hph-1 mice. β1-adrenoceptor protein was increased, as was the cAMP response to isoproterenol. Vagal function was unaffected. This places GCH1/BH4 as a regulator of sympathetic/β-adrenergic but not parasympathetic cardiac tone. hph-1 mouse model, propranolol treatment, vagal nerve stimulation, stellate ganglion stimulation, isoproterenol and forskolin responses, β1-adrenoceptor quantification, cAMP assay Cardiovascular research High 22241166
2018 l-Phenylalanine restores vascular function in spontaneously hypertensive rats through activation of the GCH1-GFRP (GCH1 feedback regulatory protein) complex, elevating vascular BH4 and improving NO bioavailability. This establishes the GCH1-GFRP complex as a pharmacologically activatable regulator of BH4 synthesis. In vivo l-phenylalanine administration in spontaneously hypertensive rats, vascular function assays, BH4 measurement JACC. Basic to translational science Medium 29963647
2007 A common GCH1 variant C+243T in the 3'-UTR decreases reporter gene expression in transfected 3'-UTR plasmids, demonstrating that this variant functionally reduces GCH1 expression and is associated with reduced renal NO excretion, altered autonomic traits (baroreceptor coupling, pulse interval), and altered blood pressure in humans. 3'-UTR reporter assay in transfected cells, twin-pair analysis of heritable traits, urinary NO/neopterin measurement, hemodynamic measurements The Journal of clinical investigation Medium 17717598
2022 GCH1/BH4 acts as a ferroptosis defense mechanism in colorectal cancer. Genetic or pharmacological inhibition of GCH1 decreases BH4, enhances lipid peroxidation, and promotes ferrous iron accumulation during erastin treatment. GCH1 knockdown specifically activates ferritinophagy (autophagy-dependent ferritin degradation) during erastin- but not RSL3-induced ferroptosis. BH4 supplementation fully rescues ferroptotic features from GCH1 knockdown. GCH1 siRNA knockdown, pharmacological inhibition, BH4 supplementation rescue, lipid peroxidation assays, ferrous iron measurement, autophagy inhibitor experiments, xenograft tumor model Frontiers in cell and developmental biology Medium 35223839
2021 GCH1 overexpression in triple-negative breast cancer reprograms tryptophan metabolism, causing L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm and kynurenine accumulation/tryptophan reduction in the supernatant. 5-HTP activates the aryl hydrocarbon receptor (AhR), which binds the IDO1 promoter to enhance IDO1 transcription, leading to increased Treg infiltration and immunosuppression. GCH1 inhibition (DAHP) reduces IDO1 expression and enhances PD-1 blockade response. Metabolomics, ChIP for AhR at IDO1 promoter, GCH1 overexpression/knockdown, in vivo tumor growth, flow cytometry for immune cells Journal for immunotherapy of cancer Medium 34281987
2022 EGFR/KRAS signaling upregulates Gch1 expression in injured dorsal root ganglion neurons, contributing to increased BH4 and neuropathic pain. EGFR inhibition suppresses GCH1 and BH4 and has analgesic effects. GCH1/BH4 also acts downstream of KRAS to drive lung cancer. These pathway relationships were identified through a phenotypic screen of ~1000 FDA-approved bioactive compounds on Gch1 expression in rodent DRG neurons. Phenotypic drug screen (~1000 compounds) on rodent DRG neurons, EGFR/KRAS inhibitor treatment, GCH1/BH4 measurement, neuropathic pain behavioral assays Science translational medicine Medium 36044597
2022 METTL3-mediated m6A modification stabilizes PBX1 mRNA. PBX1 acts as a transcription factor that directly induces GCH1 expression (confirmed by ChIP). The METTL3-PBX1-GCH1 axis increases BH4 levels in gastric cancer cells, promoting tumor proliferation and metastasis. Me-RIP sequencing, ChIP for PBX1 at GCH1 promoter, METTL3/PBX1 knockdown, BH4 ELISA, xenograft and metastasis models Cancer communications Medium 35261206
2016 AUF1 (AU-rich element RNA-binding factor 1) binds to an AU-rich element in the 3'UTR of GCH1 mRNA (validated by luciferase assay), stabilizing GCH1 mRNA and supporting its expression. AUF1 knockdown downregulates GCH1, and GCH1 knockdown suppresses proliferation and colony formation of esophageal squamous cell carcinoma cells. siRNA knockdown of AUF1, microarray profiling, 3'UTR luciferase assay for AUF1-GCH1 interaction, cell proliferation and colony formation assays International journal of oncology Medium 27826622
2019 miR-124 directly binds to the 3'UTR of GCH1 mRNA (confirmed by TargetScan prediction and luciferase reporter assay) and negatively regulates GCH1 expression in spinal cord neurons. GCH1 knockdown reduces LPS-induced spinal neuronal apoptosis. miR-124 suppresses GCH1-dependent BH4 synthesis, nitrite production, and iNOS activity, thereby inhibiting neuronal apoptosis after spinal cord injury. Luciferase reporter assay for miR-124/GCH1 3'UTR interaction, GCH1 knockdown and overexpression, flow cytometry for apoptosis, BH4/NO/iNOS measurement, rat SCI model European review for medical and pharmacological sciences Medium 31210282
2023 GCH1 silencing in LPS-stimulated Raw264.7 macrophages increases ferroptosis (elevated ROS, MDA, ferrous iron; decreased GSH, GPX4) and promotes M1 polarization (increased iNOS, IL-6, TNF-α, IL-1β; decreased CD206, IL-10). GCH1 silencing also suppresses AMPK pathway activity, linking GCH1 to AMPK-dependent ferroptosis regulation in macrophages. GCH1-specific siRNA transfection, ferroptosis markers (ROS/SOD/MDA/GSH), Western blot for AMPK/p-AMPK/GPX4/ACSL4, immunofluorescence for macrophage polarization markers Inflammation research Low 37735250
2018 miR-206 directly targets GCH1 (validated by luciferase assay in myocardial cells). miR-206 overexpression in atrial-tachypacing canines decreases GCH1 expression to ~40% and reduces BH4 and NO. GCH1 overexpression attenuated cardiac autonomic nerve remodeling (reduced PGP9.5) and increased atrial effective refractory period in tachypacing canines, placing GCH1/BH4/NO downstream of miR-206 in autonomic nerve remodeling. Luciferase reporter assay for miR-206/GCH1 interaction, lentiviral miR-206 overexpression in canine atria, GCH1 overexpression lentiviruses, BH4/NO measurement, PGP9.5 quantification Pacing and clinical electrophysiology Medium 29436714
1997 Two splice-site mutations in GCH1 (A→G at intron 1 position -2; A→G at intron 2 position -2) cause aberrant splicing: the first causes exon 2 skipping with frameshift and premature stop; the second generates a new splice acceptor site one base upstream, inserting one extra base with frameshift and premature stop. Both mutations produce truncated GTP cyclohydrolase polypeptides, establishing splice-site mutation as a molecular mechanism in DRD. RT-PCR and direct sequencing of patient mRNA, characterization of aberrant transcripts Neurogenetics Medium 10732814
2005 GCH1 activity measured in stimulated peripheral blood mononuclear cells of a patient with a novel W53X mutation was almost half the normal value (~2-20% of normal in typical HPD/DRD patients). Biopterin and neopterin in CSF were decreased. This establishes that heterozygous GCH1 nonsense mutations reduce enzymatic activity in accessible peripheral cells and explains reduced BH4 synthesis. GCH1 enzymatic activity assay in peripheral blood mononuclear cells, CSF biopterin/neopterin measurement Clinical neurology and neurosurgery Low 16289769
2023 SRSF1 binds to and upregulates circSEPT9, which blocks ubiquitination-mediated degradation of GCH1 protein, thereby increasing GCH1 protein levels and inhibiting ferroptosis in TNBC cells. The SRSF1/circSEPT9/GCH1 axis was identified using RNA immunoprecipitation and RNA pull-down assays. RNA immunoprecipitation, RNA pull-down assays, ubiquitination assays, Western blot, siRNA knockdown, ferroptosis marker measurement Journal of proteomics Low 38040194

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 165 35223839
2022 SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1. Cell death and differentiation 136 36443440
2022 CircLRFN5 inhibits the progression of glioblastoma via PRRX2/GCH1 mediated ferroptosis. Journal of experimental & clinical cancer research : CR 133 36266731
2009 Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients. Journal of neurology, neurosurgery, and psychiatry 129 19332422
2014 Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation. Free radical biology & medicine 120 25451639
2017 The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade. The Journal of investigative dermatology 83 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) 56 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 48 27217019
2018 Nicotine induces endothelial dysfunction and promotes atherosclerosis via GTPCH1. Journal of cellular and molecular medicine 47 30091833
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
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 42 29596571
2024 Inhibition of Ferroptosis by Mesenchymal Stem Cell-Derived Exosomes in Acute Spinal Cord Injury: Role of Nrf2/GCH1/BH4 Axis. Neurospine 40 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 40 36044597
2009 Autosomal dominant GTP cyclohydrolase I (AD GCH 1) deficiency (Segawa disease, dystonia 5; DYT 5). Chang Gung medical journal 35 19292934
2018 Regulation of mycobacterial infection by macrophage Gch1 and tetrahydrobiopterin. Nature communications 34 30573728
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
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
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) 30 30625990
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
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 28 22294150
2023 SRSF1 inhibits ferroptosis and reduces cisplatin chemosensitivity of triple-negative breast cancer cells through the circSEPT9/GCH1 axis. Journal of proteomics 27 38040194
2019 Liraglutide ameliorates palmitate-induced oxidative injury in islet microvascular endothelial cells through GLP-1 receptor/PKA and GTPCH1/eNOS signaling pathways. Peptides 27 31770577
2018 Common and rare GCH1 variants are associated with Parkinson's disease. Neurobiology of aging 27 30314816
1999 GCH1 mutation in a patient with adult-onset oromandibular dystonia. Neurology 27 10078749
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
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 23 34876467
2018 l-Phenylalanine Restores Vascular Function in Spontaneously Hypertensive Rats Through Activation of the GCH1-GFRP Complex. JACC. Basic to translational science 23 29963647
2016 Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway. Peptides 23 27777063
2023 GTP cyclohydroxylase1 (GCH1): Role in neurodegenerative diseases. Gene 22 37652170
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 GCH1 mutation and clinical study of Chinese patients with dopa-responsive dystonia. Movement disorders : official journal of the Movement Disorder Society 20 20108370
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
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
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) 16 37638996
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
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) 15 22293547
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
2010 Different SNP combinations in the GCH1 gene and use of labor analgesia. Molecular pain 15 20633294
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
2022 Lonicerae japonicae flos ameliorates radiotherapy-induced mesenteric artery endothelial dysfunction through GTPCH1/BH4/eNOS pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 35594639
2021 GCH1-regulated miRNAs are potential targets for microglial activation in neuropathic pain. Bioscience reports 14 34402860
2018 GCH1 attenuates cardiac autonomic nervous remodeling in canines with atrial-tachypacing via tetrahydrobiopterin pathway regulated by microRNA-206. Pacing and clinical electrophysiology : PACE 13 29436714
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
2021 Ligustilide Prevents Radiation Enteritis by Targeting Gch1/BH4/eNOS to Improve Intestinal Ischemia. Frontiers in pharmacology 12 33967762
2022 Naringenin upregulates GTPCH1/eNOS to ameliorate high glucose-induced retinal endothelial cell injury. Experimental and therapeutic medicine 11 35607381
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
2022 Splicing factor SF3B3, a NS5-binding protein, restricts ZIKV infection by targeting GCH1. Virologica Sinica 8 36572150
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
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

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