GCH1 is a zinc-dependent GTP cyclohydrolase that forms a homodecamer and converts GTP to dihydroneopterin triphosphate and formate. This cytosolic reaction supplies the pteridine precursor for tetrahydrobiopterin synthesis. GFRP couples enzyme regulation to tetrahydrobiopterin feedback and phenylalanine availability. The resulting cofactor supports nitric oxide synthases and aromatic amino-acid hydroxylases. Nuclear enzyme activity is also reported in human epidermal cells. Alternative splicing produces four proteins with distinct C termini. Pathogenic variants cause dopa-responsive dystonia and BH4-deficient hyperphenylalaninemia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003924 GTPase activity | IDA PMID:2463916 Purification of GTP cyclohydrolase I from human liver and pr... | UNDECIDED | Summary: The positive GTPase assertion remains unresolved. Reason: GO:0003924 requires GDP and phosphate production. The human-liver abstract does not expose that assay; full text remains unavailable. Canonical cyclohydrolase chemistry retains triphosphate but cannot exclude an additional activity in unread experiments. Retain the positive qualifier and uncertainty. |
| GO:0003934 GTP cyclohydrolase I activity | EXP PMID:2463916 Purification of GTP cyclohydrolase I from human liver and pr... | ACCEPT | Summary: Human-liver enzyme purification supports the core reaction. Reason: The purified human-liver enzyme supports the catalytic assertion, independently corroborated by modern human chemistry. Exact natural-product identity and historical oligomer estimates remain unverified. |
| GO:0003934 GTP cyclohydrolase I activity | EXP PMID:3753653 The application of 8-aminoguanosine triphosphate, a new inhi... | ACCEPT | Summary: Human-liver substrate kinetics support cyclohydrolase activity. Reason: The paper reports purified human-liver enzyme activity, GTP kinetics and competitive inhibition by a GTP analogue. These observations support the established catalytic function. The older statement that no added cofactors were required does not demonstrate absence of a tightly bound zinc ion. |
| GO:0003934 GTP cyclohydrolase I activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the inherited GTP cyclohydrolase I activity. Reason: The actual PAINT assertion at PTN000121833 lies on the verified path to human P30793 in PTHR11109. Human enzyme experiments independently establish the same reaction, supporting retention of this conserved catalytic activity. The literal donor list and ancestral placement are preserved; no target-specific loss of this activity is indicated. |
| GO:0003934 GTP cyclohydrolase I activity | IDA PMID:16778797 GTP cyclohydrolase feedback regulatory protein controls cofa... | ACCEPT | Summary: Retain catalytic activity with its literal nuclear context. Reason: The authentic abstract reports GTP cyclohydrolase I activity in nuclei of human epidermal keratinocytes and melanocytes. This supports the enzyme activity with the original nucleus extension. It does not establish the same nuclear distribution in every cell type or resolve the physiological purpose of that pool. Supporting Evidence: |
| GO:0003934 GTP cyclohydrolase I activity | IDA PMID:7730309 Characterization of mouse and human GTP cyclohydrolase I gen... | ACCEPT | Summary: Retain the activity assayed during human mutation analysis. Reason: The authentic abstract reports patient GCH1 mutations and activity testing of recombinant enzymes in Escherichia coli. The catalytic annotation agrees with independently demonstrated human GCH1 activity. Exact constructs, individual variant activities and modern isoform identities are not established from this abstract alone. |
| GO:0003934 GTP cyclohydrolase I activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic mapping identifies the established catalytic activity. Reason: The combined electronic mappings identify GTP cyclohydrolase I activity, independently demonstrated for human GCH1. It converts GTP into dihydroneopterin triphosphate and formate. This acceptance rests on the verified target reaction; it does not imply that every contributing electronic rule was separately reconstructed. |
| GO:0005515 protein binding | IPI PMID:16696853 A yeast 2-hybrid analysis of human GTP cyclohydrolase I prot... | REMOVE | Summary: Preserve AHSA1 interaction evidence without the generic label. Reason: AHSA1 binding is positive in yeast and GST pull-down. Remove the uninformative protein-binding label without denying that interaction or assigning GCH1 an HSP90 chaperone role. |
| GO:0005515 protein binding | IPI PMID:16696853 A yeast 2-hybrid analysis of human GTP cyclohydrolase I prot... | REMOVE | Summary: GCH1 associates with the HSP90 cochaperone AHSA1. Reason: Human GCH1 binds AHSA1 in the original yeast screen and GST pull-down. This establishes an association with an HSP90 cochaperone, but does not assign GCH1 chaperone activity. Remove the generic protein-binding term while retaining the positive interaction and its assay limits. |
| GO:0005515 protein binding | IPI PMID:16696853 A yeast 2-hybrid analysis of human GTP cyclohydrolase I prot... | REMOVE | Summary: Keep the regulatory association distinct from generic protein binding. Reason: Human GCH1βrat GFRP binding was tested in this paper; independent human structures support the regulatory complex. Remove the generic label while preserving this functional association and the tested species. |
| GO:0005515 protein binding | IPI PMID:19294699 Proteomic analysis of GTP cyclohydrolase 1 multiprotein comp... | MODIFY | Summary: Specify binding to the serine/threonine kinase CK2 alpha. Reason: The source reports CK-IIalpha among proteins associated with GCH1 in human astrocytes. P68400 is the catalytic serine/threonine-kinase subunit, supporting GO:0120283 through an actual is_a refinement. Preserve the astrocyte extension and co-immunoprecipitation scope; this does not assign kinase activity to GCH1. A separate endothelial study implicates CK2 alpha-prime in Ser81 regulation; it does not replace this alpha-subunit interaction evidence. Proposed replacements: protein serine/threonine kinase binding |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MODIFY | Summary: Specify the experimentally supported 14-3-3 interaction. Reason: The exact GCH1βYWHAZ row in original Table S2 reports positive yeast, pull-down, co-IP and co-localization results. The independently verified partner class supports GO:0071889, an is_a descendant of protein binding. No specific phosphorylation-dependent mechanism or physiological effect is inferred. Proposed replacements: 14-3-3 protein binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Preserve the transportin-2 screen pair without generic annotation. Reason: The original screen identifies P30793-1 with O14787-2. Preserve that positive pair and its product labels while removing the uninformative protein-binding term. Binding alone does not establish that transportin-2 imports GCH1. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Preserve the transportin-3 screen pair without generic annotation. Reason: The original screen identifies P30793-1 with Q9Y5L0-2, whereas the incoming fields remain gene-level. Preserve that distinction and positive pair; remove generic protein binding without asserting a GCH1 transport mechanism. |
| GO:0005515 protein binding | IPI PMID:9092499 GTP cyclohydrolase I feedback regulatory protein is a pentam... | REMOVE | Summary: Retain GFRP regulation without a generic binding label. Reason: The authentic abstract reports rat GFRP purification and a proposed GFRPβGCH1 assembly model. Independent human structures confirm the association. Remove the uninformative protein-binding label without treating the GFRP-focused citation as evidence against the interaction. |
| GO:0005525 GTP binding | IDA PMID:14717702 GTP cyclohydrolase I utilizes metal-free GTP as its substrat... | ACCEPT | Summary: GTP recognition is a direct substrate-binding property. Reason: Purified recombinant human GCH1 was shown to use metal-free GTP. This supports GTP binding as part of the core catalytic mechanism. Reduced activity at high divalent-cation concentrations reflects substrate availability in the inspected abstract; it should not be conflated with loss of the enzyme-bound zinc cofactor. Supporting Evidence: |
| GO:0005525 GTP binding | IDA PMID:3753653 The application of 8-aminoguanosine triphosphate, a new inhi... | ACCEPT | Summary: Substrate kinetics and competitive inhibition support GTP binding. Reason: Human-liver enzyme GTP kinetics and competitive inhibition by 8-aminoguanosine triphosphate support substrate recognition. Retain this molecular property of the established enzyme without inferring a signaling-GTPase mechanism. Supporting Evidence: |
| GO:0005634 nucleus | IDA PMID:16778797 GTP cyclohydrolase feedback regulatory protein controls cofa... | KEEP AS NON CORE | Summary: Human epidermal cells contain nuclear GCH1 activity. Reason: The authentic abstract reports GCH1 in human epidermal-cell nuclei with cyclohydrolase activity. Retain the positive nuclear location while leaving its physiological purpose and generality beyond those cells unresolved. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain the experimentally supported nuclear pool. Reason: The UniProt nuclear-location mapping is independently supported by the reported human epidermal nuclear activity and HPA localization. Keep this additional compartment without assigning an untested nuclear physiological role or assuming all cell types have the same distribution. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Retain the HPA nucleoplasmic observation. Reason: The current target-specific HPA text assigns supported nucleoplasmic localization with antibody HPA028612 in the listed human cell lines. Retain the experimental compartment without claiming independent image or antibody-specificity verification, or a separate nuclear molecular function. Supporting Evidence: GO_REF:0000052 |
| GO:0005737 cytoplasm | EXP PMID:12176133 GTP cyclohydrolase I gene transfer augments intracellular te... | MODIFY | Summary: Refine the broad compartment with independent human cytosolic evidence. Reason: The original gene-transfer abstract supports functional human GCH1 but does not expose a localization assay. Independent HPA and human Reactome evidence support cytosol as a part_of refinement; this does not pretend the source Methods were independently inspected. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | EXP PMID:16778797 GTP cyclohydrolase feedback regulatory protein controls cofa... | MODIFY | Summary: Resolve the cytoplasmic pool to cytosol while retaining nuclear evidence separately. Reason: Human epidermal GCH1 has both cytoplasmic and nuclear source context. Independent human cytosolic localization supports this part_of refinement of the broad cytoplasm row; it does not remove the separately retained nuclear annotation. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | EXP PMID:2463916 Purification of GTP cyclohydrolase I from human liver and pr... | MODIFY | Summary: Specify the established cytosolic enzyme pool. Reason: Independent human HPA and Reactome evidence resolve the unqualified compartment to cytosol. The cited purification is consistent with soluble enzyme; its historical fractionation protocol remains uninspected. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Refine the conserved cytoplasmic placement using independent human location evidence. Reason: The actual cytoplasm IBD is ancestral to human GCH1; its self-donor is valid experimental grounding. Independent human HPA and Reactome evidence supports the cytosolic pool, a part_of refinement. This does not claim a cytosol-specific ancestral assertion or failure of the original PAINT placement. Proposed replacements: cytosol Supporting Evidence: GO_REF:0000033 GO_REF:0000052 Reactome:R-HSA-1474146 |
| GO:0005737 cytoplasm | IDA PMID:10907721 Specific localization of the guanosine triphosphate (GTP) cy... | MODIFY | Summary: Use cytosol for the independently supported intracellular pool. Reason: The authentic human-brain abstract reports GCH1 staining in neuronal bodies and fibers. Independent target-specific cytosolic evidence justifies the gene-level refinement; the abstract alone does not resolve intracellular topology or establish localization specifically at projection termini. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Specify the well-supported cytosolic pool. Reason: The UniProt cytoplasm mapping agrees with a soluble cytosolic enzyme pool independently represented by HPA and accession-resolved Reactome models. Refine this unqualified gene-level assertion along the actual cytosol part_of cytoplasm relation; the separate nuclear pool is retained. Proposed replacements: cytosol Supporting Evidence: GO_REF:0000044 GO_REF:0000052 Reactome:R-HSA-1474146 |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Retain the human cytosolic localization. Reason: The HPA target page explicitly reports supported cytosolic staining in human U251MG and U2OS cells, consistent with the metabolic enzyme pool. The text and cell-line assignments were read; image pixels and antibody validation were not independently reanalyzed. Supporting Evidence: GO_REF:0000052 |
| GO:0005829 cytosol | IDA PMID:2463916 Purification of GTP cyclohydrolase I from human liver and pr... | ACCEPT | Summary: Retain cytosol as the supported human enzyme compartment. Reason: Independent human localization supports this compartment. The cited human-liver preparation is consistent with it, while full historical fractionation details remain unavailable. |
| GO:0005829 cytosol | IDA PMID:3318829 Localization of GTP cyclohydrolase I in human peripheral blo... | ACCEPT | Summary: Human blood-cell staining supports the intracellular enzyme pool. Reason: The authentic abstract reports strong intraplasmatic staining with a human-specific monoclonal antibody in several blood-cell classes. Defer to the curated cytosolic assignment, independently supported elsewhere, without claiming that the abstract resolves every subcompartment. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Retain the cytosolic compartment of active GCH1. Reason: The transferred cytosolic location agrees with independent human localization and the accession-resolved active Reactome complex. Preserve the literal is_active_in relation; the mouse transfer is not being relabeled as a new human experiment. Supporting Evidence: GO_REF:0000107 GO_REF:0000052 Reactome:R-HSA-1474146 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1474146 | ACCEPT | Summary: The human catalytic model places GCH1 in cytosol. Reason: The actual reaction-to-catalyst-to-decamer-to-dimer chain reaches human P30793 residues 1β250 in cytosol. Retain the modeled location; it is an inspected curated model, not an independently performed localization assay. Supporting Evidence: Reactome:R-HSA-1474146 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1474158 | ACCEPT | Summary: The human regulatory complex contains cytosolic GCH1. Reason: The actual input/output-complex chains reach human P30793 in cytosol. GCHFR is the modeled inhibitor, whereas GCH1 is its target and complex constituent. This supports location without transferring the partner inhibitor activity to GCH1. Supporting Evidence: Reactome:R-HSA-1474158 |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: BH4 synthesis is a conserved direct biosynthetic role. Reason: GCH1 catalyzes the first chemical step of BH4 synthesis. The actual PAINT placement is ancestral to the human target and includes valid target experimental grounding; the self-donor is not circular. Retain the conserved pathway annotation. |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IDA PMID:7678411 Pteridine biosynthesis in human endothelial cells. Impact on... | ACCEPT | Summary: Human endothelial assays establish BH4 biosynthesis. Reason: The authentic abstract reports increased GCH1 activity with BH4 accumulation in HUVECs. This agrees with its direct catalytic role in the pathway, rather than merely an unrelated expression correlation. |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IDA PMID:9445252 Cytokines stimulate GTP cyclohydrolase I gene expression in ... | ACCEPT | Summary: Cytokine-induced enzyme activity supports BH4 synthesis. Reason: The authentic abstract reports increased GCH1 transcription, enzyme activity and BH4 production in human endothelial cells. Retain the directly established biosynthetic role. Supporting Evidence: |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IMP PMID:17101830 Novel mutations in the guanosine triphosphate cyclohydrolase... | ACCEPT | Summary: Human deficiency findings support the established BH4 pathway. Reason: The clinical study associates GCH1 variants with reduced cerebrospinal biopterin measurements. Independent human enzyme evidence establishes direct pathway participation. Retain BH4 biosynthesis without claiming that every patient variant or natural product was independently assayed. |
| GO:0006729 tetrahydrobiopterin biosynthetic process | IMP PMID:19666465 Critical role for tetrahydrobiopterin recycling by dihydrofo... | ACCEPT | Summary: GCH1 directly controls BH4 production. Reason: The original distinguishes human GCH1 in murine fibroblasts from endogenous murine endothelial knockdown. Both support BH4 production; independent human endothelial gene-transfer evidence supports the retained endothelial context. Preserve that atom without misidentifying the source experiments as human endothelial cells. |
| GO:0006809 nitric oxide biosynthetic process | NAS PMID:9445252 Cytokines stimulate GTP cyclohydrolase I gene expression in ... | MARK AS OVER ANNOTATED | Summary: BH4 supply regulates NOS rather than synthesizing NO directly. Reason: GCH1 makes a BH4 precursor; NOS performs NO-forming chemistry. The source supports cofactor supply and cytokine regulation, not a GCH1-catalyzed NO step. Preserve the positive regulatory connection through the separately supported NOS-activity annotations. |
| GO:0008217 regulation of blood pressure | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Retain blood-pressure regulation as a contextual consequence of cofactor supply. Reason: GCH1-dependent BH4 availability influences NOS function, and the independent human study relates GCH1 variation to vascular physiology and blood-pressure extremes. This supports a non-core regulatory role. The ARBA identifier is retained, while its complete condition branch has not been reconstructed. |
| GO:0008217 regulation of blood pressure | IMP PMID:17717598 Discovery of common human genetic variants of GTP cyclohydro... | KEEP AS NON CORE | Summary: Human data support a contextual vascular regulatory role. Reason: The original reports genotype associations with NO metabolites and blood-pressure extremes, plus a human UTR reporter. Retain regulation of blood pressure with its population and association limits; do not turn the reporter into a direct arterial-pressure perturbation experiment. Supporting Evidence: |
| GO:0008270 zinc ion binding | IDA PMID:11087827 Zinc plays a key role in human and bacterial GTP cyclohydrol... | ACCEPT | Summary: The human enzyme directly coordinates catalytic zinc. Reason: The inspected original human structure and atomic-absorption results establish an active-site zinc ion. Retain this catalytic cofactor-binding property, with the engineered Ξ42 construct distinguished from natural short products. Supporting Evidence: |
| GO:0008270 zinc ion binding | IDA PMID:14717702 GTP cyclohydrolase I utilizes metal-free GTP as its substrat... | ACCEPT | Summary: Zinc occupancy and refolding experiments support zinc binding. Reason: The human recombinant enzyme contained approximately one zinc atom per subunit, and zinc supported recovery of activity during chaperone-assisted refolding. These reported results support zinc binding integral to the catalytic enzyme; they do not establish activities of all natural short products. Supporting Evidence: |
| GO:0010460 positive regulation of heart rate | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the conserved heart-rate effect with the mouse developmental scope. Reason: The traced mouse Gch1-null study measures bradycardia at E11.5, alongside reduced BH4 and L-DOPA. This supports the transferred physiological regulation at non-core scope. The authors allow secondary failing-heart effects; no direct pacemaker mechanism or heart-rate rescue is established by the inspected survival-rescue experiment. |
| GO:0031410 cytoplasmic vesicle | IDA PMID:3318829 Localization of GTP cyclohydrolase I in human peripheral blo... | UNDECIDED | Summary: The vesicle-specific localization remains unverified. Reason: The authentic blood-smear abstract reports intraplasmatic and reticulated staining but does not expose a vesicle-specific assay. Original full-text retrieval failed. Keep this curator assertion unresolved rather than infer absence, reinterpret reticular staining as vesicles, or claim miscitation. Supporting Evidence: |
| GO:0031965 nuclear membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Retain the supported HPA nuclear-envelope pool. Reason: The target-specific HPA text reports supported nuclear-membrane localization in U2OS cells. Retain the observation without requiring a transmembrane segment or known membrane-specific physiology; no independent image or isoform assignment is claimed. Supporting Evidence: GO_REF:0000052 |
| GO:0032496 response to lipopolysaccharide | IDA PMID:7678411 Pteridine biosynthesis in human endothelial cells. Impact on... | KEEP AS NON CORE | Summary: Retain the reported endothelial LPS response. Reason: Original HUVEC Results show increased GCH1 activity and intracellular pterins after LPS. Preserve this measured response; the separate protein-expression result has a different endpoint (see the NOT-row exception). Supporting Evidence: |
| GO:0032496 response to lipopolysaccharide | IDA PMID:9445252 Cytokines stimulate GTP cyclohydrolase I gene expression in ... | UNDECIDED | Summary: The LPS-specific experiment is not resolved for this citation. Reason: The abstract describes cytokine treatment without exposing an LPS assay. Full text is unavailable, so retain source-specific uncertainty without alleging miscitation. Supporting Evidence: |
| GO:0032496 response to lipopolysaccharide | IEP NOT PMID:15604419 Cytokine-stimulated GTP cyclohydrolase I expression in endot... | KEEP AS NON CORE | Summary: Retain the conditional absence of an LPS response. Reason: The original HUVEC Results report no GCH1 protein induction with LPS alone or added to cytokines (data not shown). Preserve this conditional expression result, not universal LPS unresponsiveness. |
| GO:0032991 protein-containing complex | IDA PMID:11087823 3' deletions cause aniridia by preventing PAX6 gene expressi... | MODIFY | Summary: Specify the catalytic GCH1 homodecamer and preserve the reference defect. Reason: Independent human structural studies establish the catalytic homodecamer, represented by GO:0034615 GCH1 complex. Its verified is_a path reaches protein-containing complex. The original PMID:11087823 instead studies PAX6 cis-regulation; retain its WRONG_REFERENCE defect without guessing an intended replacement citation. GFRP association remains a regulatory property, not a newly proposed complex term. Proposed replacements: GCH1 complex |
| GO:0034341 response to type II interferon | IDA PMID:12607127 Role of human GTP cyclohydrolase I and its regulatory protei... | KEEP AS NON CORE | Summary: GCH1 expression responds to interferon-gamma. Reason: The authentic abstract reports increased GCH1 mRNA after interferon-gamma stimulation of HUVECs. This meets the response term, which includes altered gene expression, but is a contextual regulation of the enzyme rather than its defining catalytic activity. Supporting Evidence: |
| GO:0034341 response to type II interferon | IDA PMID:7678411 Pteridine biosynthesis in human endothelial cells. Impact on... | KEEP AS NON CORE | Summary: Interferon stimulation changes endothelial GCH1 activity. Reason: The authentic abstract reports interferon-gamma effects on GCH1 activity and BH4 abundance. Retain the response with its endothelial experimental context, without assigning GCH1 the upstream cytokine-signaling machinery. Supporting Evidence: |
| GO:0034341 response to type II interferon | IDA PMID:9445252 Cytokines stimulate GTP cyclohydrolase I gene expression in ... | KEEP AS NON CORE | Summary: Retain interferon-associated regulation in the tested cytokine conditions. Reason: Human endothelial GCH1 transcription and activity increase in the reported cytokine treatment including interferon-gamma. Preserve the response without claiming an independently isolated effect from the abstract alone. Supporting Evidence: |
| GO:0034612 response to tumor necrosis factor | IDA PMID:9445252 Cytokines stimulate GTP cyclohydrolase I gene expression in ... | KEEP AS NON CORE | Summary: Retain TNF-associated regulation in the tested cytokine conditions. Reason: The reported cytokine treatment includes TNF and increases GCH1 expression and activity. Retain this response, with the mixture and abstract-only access explicit. Supporting Evidence: |
| GO:0042416 dopamine biosynthetic process | IDA PMID:16338639 The assays of activities and function of TH, AADC, and GCH1 ... | MARK AS OVER ANNOTATED | Summary: Cofactor supply enhances dopamine production without performing its carbon-conversion steps. Reason: Human GCH1 co-expression increases dopamine output in the reported engineered-cell system, preserving positive functional coupling. GCH1 supplies a BH4 precursor; TH and AADC perform the dopamine-forming reactions. The endpoint does not establish GCH1 itself executing those biosynthetic steps. |
| GO:0042558 pteridine-containing compound metabolic process | IEA GO_REF:0000117 | MODIFY | Summary: Specify pteridine biosynthesis while preserving its broader product scope. Reason: Human GCH1 synthesizes a pterin-ring precursor, and human endothelial experiments measure neopterin as well as BH4 accumulation. Refine general metabolism to the directly supported biosynthetic child. This retains pteridine breadth instead of implying that every measured pterin is BH4. Proposed replacements: pteridine-containing compound biosynthetic process |
| GO:0042559 pteridine-containing compound biosynthetic process | IDA PMID:15721862 Augmented BH4 by gene transfer restores nitric oxide synthas... | ACCEPT | Summary: Pteridine formation is a direct consequence of the catalytic reaction. Reason: The gene-transfer study increases cellular biopterins and BH4. GCH1 directly forms dihydroneopterin triphosphate, and other human experiments also report neopterin accumulation. Retain the meaningful pteridine-biosynthesis scope rather than discard that chemistry when the BH4 child is also represented. |
| GO:0042559 pteridine-containing compound biosynthetic process | IDA PMID:2463916 Purification of GTP cyclohydrolase I from human liver and pr... | ACCEPT | Summary: Human-liver enzyme activity supports direct pteridine formation. Reason: Active purified cyclohydrolase and modern human reaction chemistry support direct pteridine formation. Full historical Methods and exact construct identity remain uninspected. |
| GO:0042559 pteridine-containing compound biosynthetic process | IDA PMID:3753653 The application of 8-aminoguanosine triphosphate, a new inhi... | ACCEPT | Summary: Retain direct synthesis of the pteridine precursor. Reason: The human-liver substrate-kinetic study supports the established cyclohydrolase reaction, whose product is a pteridine-containing precursor. This broader synthesis assertion remains biologically informative alongside BH4 synthesis; it does not imply human GCH1 performs every pteridine pathway. |
| GO:0042802 identical protein binding | IPI PMID:11087827 Zinc plays a key role in human and bacterial GTP cyclohydrol... | MODIFY | Summary: Specify self-binding that contributes to homodimer assembly. Reason: Human structural and interaction evidence supports dimer interfaces within the active homodecamer. GO:0042803 is an actual is_a descendant of identical protein binding. This refinement does not imply that the isolated dimer is the active enzyme. Proposed replacements: protein homodimerization activity |
| GO:0042803 protein homodimerization activity | IPI PMID:16696853 A yeast 2-hybrid analysis of human GTP cyclohydrolase I prot... | ACCEPT | Summary: Retain homodimerization within the decameric enzyme assembly. Reason: Human self-interaction and deletion experiments, interpreted with the structural assembly, support dimer formation. The dimers contribute to a decamer; the active enzyme is not asserted to be merely dimeric. |
| GO:0044306 neuron projection terminus | TAS PMID:23457032 The neurobiology of tetrahydrobiopterin biosynthesis: a mode... | UNDECIDED | Summary: The dopaminergic-terminal claim needs its supporting full-text passage. Reason: The authentic review abstract establishes monoaminergic-neuron context but does not describe GCH1 protein localization at projection termini. The full route remained abstract-only. Preserve the literal dopaminergic-neuron extension and unresolved TAS assertion; do not substitute BH4 localization or neuron-wide expression for the specific protein compartment. Supporting Evidence: |
| GO:0046146 tetrahydrobiopterin metabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Specify the biosynthetic contribution to BH4 metabolism. Reason: Independent human enzyme and gene-transfer data establish BH4 synthesis. The verified is_a child captures that contribution more precisely than general BH4 metabolism, without assigning GCH1 the distinct recycling reactions performed by other enzymes. Proposed replacements: tetrahydrobiopterin biosynthetic process |
| GO:0046654 tetrahydrofolate biosynthetic process | IEA GO_REF:0000002 | REMOVE | Summary: The unrestricted family mapping transfers the wrong downstream pathway. Reason: Both contributing InterPro entries map tetrahydrofolate biosynthesis, but their own descriptions distinguish prokaryotic folate synthesis from vertebrate BH4 synthesis. Conserved GTP-to-dihydroneopterin-triphosphate chemistry does not establish human GCH1 participation in tetrahydrofolate formation. Remove this electronic process transfer, without denying family membership, conserved catalysis or human folate-derivative metabolism. Supporting Evidence: GO_REF:0000002 InterPro:IPR001474 InterPro:IPR018234 UniProtKB:P30793 |
| GO:0048265 response to pain | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain the pain-context response with its donor and assay limits. Reason: The traced rat source reports increased GCH1/BH4 after injury or inflammation and effects of pathway inhibition or intrathecal BH4 on pain. Separate human haplotype findings corroborate context. Retain the response without claiming a direct sensory receptor, verified inhibitor specificity or an established human perturbational mechanism. |
| GO:0050884 neuromuscular process controlling posture | IMP PMID:7874165 Hereditary progressive dystonia with marked diurnal fluctuat... | KEEP AS NON CORE | Summary: Retain the upstream contribution to postural control. Reason: The original human disease report links GCH1 mutations and reduced enzyme activity to dopa-responsive dystonia. The literal acts_upstream_of_or_within relation accommodates its upstream metabolic contribution. Retain that qualified non-core association without changing it to direct execution of motor control. Supporting Evidence: |
| GO:0051000 positive regulation of nitric-oxide synthase activity | IDA PMID:12176133 GTP cyclohydrolase I gene transfer augments intracellular te... | KEEP AS NON CORE | Summary: BH4 supply increases NOS activity in human endothelial cells. Reason: Human GCH1 gene transfer increases BH4 and eNOS-specific NO output, with enhanced eNOS dimerization. This supports positive regulation through cofactor availability, without assigning GCH1 NOS catalysis or direct GCH1βNOS binding. Supporting Evidence: |
| GO:0051000 positive regulation of nitric-oxide synthase activity | IDA PMID:15721862 Augmented BH4 by gene transfer restores nitric oxide synthas... | KEEP AS NON CORE | Summary: GCH1-dependent BH4 replenishment restores endothelial NOS function. Reason: The authentic abstract reports GCH1 gene transfer, increased BH4 and NO output, reduced superoxide production and improved eNOS dimerization in hyperglycemic human endothelial cells. Retain this contextual positive regulation, not a claim that GCH1 catalyzes NO formation. Supporting Evidence: |
| GO:0051000 positive regulation of nitric-oxide synthase activity | IMP PMID:17717598 Discovery of common human genetic variants of GTP cyclohydro... | KEEP AS NON CORE | Summary: Retain NOS regulation with the human association study kept in scope. Reason: The original links GCH1 variation to urinary NO metabolites and tests a human UTR reporter; it does not directly assay NOS catalysis. Independent human endothelial gene-transfer results substantiate the regulatory function. Keep the original evidence fields and the source-specific assay distinction. |
| GO:0051019 mitogen-activated protein kinase binding | IPI PMID:19294699 Proteomic analysis of GTP cyclohydrolase 1 multiprotein comp... | KEEP AS NON CORE | Summary: Retain the reported MAPK12 association in astrocytes. Reason: The authentic abstract specifically reports MAPK12 association with active GCH1 after cytokine treatment in adult human astrocytes. Retain the literal cell context as a non-core interaction. Co-immunoprecipitation does not establish purified binary binding or a MAPK signaling activity performed by GCH1. |
| GO:0051019 mitogen-activated protein kinase binding | IPI PMID:19294699 Proteomic analysis of GTP cyclohydrolase 1 multiprotein comp... | KEEP AS NON CORE | Summary: Retain the reported JNK3 association in astrocytes. Reason: The same study explicitly identifies JNK3 among the GCH1-associated proteins in cytokine-treated human astrocytes. Retain this contextual MAP-kinase interaction and the original extension. Its regulatory mechanism and directness are not independently resolved by the inspected abstract. |
| GO:2000121 regulation of removal of superoxide radicals | IMP PMID:19666465 Critical role for tetrahydrobiopterin recycling by dihydrofo... | MARK AS OVER ANNOTATED | Summary: Reduced superoxide production does not establish radical removal. Reason: The original GCH1 perturbations alter BH4 availability and eNOS-derived superoxide production. GO:2000121 concerns removal of existing radicals, a distinct process. The MTX antioxidant-capacity result does not establish GCH1-mediated removal. Preserve the positive NOS-coupling mechanism and original endothelial context. Supporting Evidence: |
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Download this section (compressed HTML)Q: Does the positive human-liver GTPase annotation reflect an independently demonstrated GDP-producing reaction in the original PMID:2463916 experiments?
Q: What are the activity, assembly and cellular distribution of sequence-verified natural GCH-4, relative to the other three products?
Q: Which original target-specific experiments support the vesicle and dopaminergic presynaptic-terminal placements?
Experiment: Compare all four sequence-verified natural proteins for dihydroneopterin triphosphate and formate production and oligomer assembly. Analyze engineered N-terminal truncations separately.
Type: Natural-product activity and assembly
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