{"gene":"G6PC1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2025,"finding":"Cryo-EM structures of human G6PC1 were solved in apo (partially open) and fully open states, and in complex with substrates G6P or F6P and product phosphate. G6PC1 comprises nine transmembrane helices with a large catalytic pocket facing the ER lumen. Substrate binding induces substantial conformational rearrangements (induced-fit mechanism) in the catalytic pocket that facilitate sugar moiety binding. The structures also reveal a potential mechanism by which phosphatidylserine regulates G6PC1 activity.","method":"Cryo-EM structure determination with functional analysis; substrate-bound and apo forms resolved","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures in multiple states (apo, substrate-bound, product-bound) with functional validation in a single rigorous study","pmids":["40664655"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of wild-type human G6PC1 (apo) and a catalytic mutant G6PC1-H176A bound to G6P were solved, revealing nine transmembrane helices, a large catalytic pocket facing the ER lumen, and that G6P binding induces substantial conformational rearrangements in the catalytic pocket facilitating sugar moiety binding.","method":"Cryo-EM structure determination of wild-type apo and H176A mutant + G6P complex, with functional analyses","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM with active-site mutagenesis and substrate-bound structure in one rigorous study","pmids":["39847333"],"is_preprint":false},{"year":1999,"finding":"Four missense mutations in G6PC (W77R, A124T, G184E, L211P) were individually introduced by site-directed mutagenesis and expressed in COS-7 cells; all four mutations completely abolished G6PC enzymatic (glucose-6-phosphatase) activity, establishing these residues as functionally critical.","method":"In vitro expression system (COS-7 cells), site-directed mutagenesis, enzymatic activity assay","journal":"Annals of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with active-site mutagenesis and enzymatic assay in a single focused study","pmids":["10738525"],"is_preprint":false},{"year":2008,"finding":"G6PC encodes glucose-6-phosphatase-alpha, a highly hydrophobic glycoprotein anchored in the ER membrane with its active center facing the ER lumen, catalyzing hydrolysis of glucose-6-phosphate to glucose and phosphate. Functional characterization of 50 missense, 2 nonsense, and 2 insertion/deletion mutations confirmed their effects on enzymatic activity and protein stability, establishing structure-function relationships across the protein.","method":"Compiled functional characterization from heterologous expression and enzymatic assays across multiple studies; topology established by biochemical analysis","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic assays and mutagenesis replicated across many studies and summarized in this comprehensive review","pmids":["18449899"],"is_preprint":false},{"year":2021,"finding":"A panel of 29 G6PC coding variants was heterologously expressed as fusion proteins in a hepatocyte-derived cell line. The screen revealed variant effects on steady-state protein levels, N-linked glycosylation status, and intracellular distribution. The VUS p.Cys109Tyr exhibited significantly reduced protein levels, altered glycosylation, and abnormally diffuse localization, consistent with pathogenicity.","method":"Heterologous expression of fusion proteins, Western blot for protein levels and glycosylation, immunofluorescence for intracellular distribution","journal":"JIMD reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (protein levels, glycosylation, localization) in a single lab study","pmids":["34258141"],"is_preprint":false},{"year":2019,"finding":"A single amino acid substitution S298C in human G6PC (rAAV-G6PC-S298C) increased enzymatic efficacy approximately 3-fold compared to native G6PC in G6pc-/- mice, demonstrating that position 298 influences G6PC activity level in vivo. Restoring ≥3% of normal hepatic G6Pase-alpha activity prevented hepatocellular adenoma/carcinoma development, and G6Pase-alpha deficiency leads to hepatic autophagy impairment that can contribute to hepatocarcinogenesis.","method":"In vivo gene transfer in G6pc-/- mice, hepatic G6Pase activity assay, long-term (66-week) phenotypic characterization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo activity assay with engineered variant and long-term phenotypic readout, single lab","pmids":["32430177"],"is_preprint":false},{"year":2021,"finding":"The Mediator complex kinase module subunit MED13 is required for transcriptional activation of G6pc by fructose in the liver. In liver-specific MED13 knockout mice, ChREBP binding to the G6pc promoter was dramatically reduced and ChREBP-beta and FOXO1 transcriptional activities were suppressed, while FOXO1 binding to the G6pc promoter was unaffected. This establishes that MED13/Mediator kinase module is necessary for ChREBP-dependent G6pc transcription and consequent regulation of liver glycogen levels.","method":"Liver-specific MED13 knockout mice, G6PC enzymatic activity assay, ChIP assay at G6pc promoter, transcriptional activity assays in hepatocytes, glycogen measurements","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with ChIP and enzymatic assays, multiple orthogonal methods in single lab","pmids":["33812059"],"is_preprint":false},{"year":2025,"finding":"METTL14, in complex with METTL3, installs N6-methyladenosine (m6A) on G6pc mRNA at five sites. m6A readers YTHDF1 and YTHDF3 (but not YTHDF2) bind to m6A-marked G6pc mRNA to increase both its stability and translation, thereby increasing G6PC protein levels and hepatic glucose production. Deletion of five m6A sites (G6pcΔ5A) blocked METTL14-induced effects. Liver-specific Mettl14 knockout decreased G6pc expression and gluconeogenesis; hepatocyte-specific G6pc restoration reversed defective hepatic glucose production in Mettl14 KO mice.","method":"In vitro m6A methylation, METTL14 KO and OE in hepatocytes and mice, m6A site mutagenesis (G6pcΔ5A), RIP assays, mRNA stability assay, glucose production assay, genetic rescue experiment","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (m6A mutagenesis, YTHDF RIP, KO + rescue, in vitro and in vivo) in a single rigorous study","pmids":["40278833"],"is_preprint":false},{"year":2017,"finding":"A 3'-UTR SNP rs2229611 in G6PC1 reduces mRNA stability and decreases expression. In HepG2 cells, luciferase constructs bearing the rs2229611 allele showed significantly decreased expression compared to wild-type 3'-UTR, due to reduced mRNA stability mediated by AU-rich elements (AREs). miRNAs also showed more distinct inhibition of reporter function with rs2229611. This demonstrates a post-transcriptional regulatory mechanism for G6PC1 expression.","method":"Luciferase reporter assay in HepG2 cells, 3'-UTR deletion constructs, pmirGLO-UTR constructs for miRNA effects","journal":"Clinica chimica acta; international journal of clinical chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple reporter constructs with orthogonal approaches (deletion series, miRNA reporters) in single lab","pmids":["28502559"],"is_preprint":false},{"year":2023,"finding":"Retinaldehyde (Rald) downregulates G6PC expression by antagonizing retinoid X receptor alpha (RXRα) at direct repeat 1 (DR1) response elements in the G6PC/PCK1 promoters. This was confirmed by luciferase reporter assays and molecular docking. In primary human hepatocytes and HepG2 cells, Rald treatment decreased G6PC mRNA and protein expression and reduced glucose production.","method":"Luciferase reporter assays (DR1 elements), molecular docking, primary human hepatocyte experiments, mRNA/protein quantification","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, docking, primary human hepatocytes) in single lab","pmids":["37719384"],"is_preprint":false},{"year":2023,"finding":"miR-494 targets G6pc mRNA in hepatocellular carcinoma cells, inducing a metabolic shift toward glycolytic phenotype through G6pc repression and HIF-1A pathway activation. The miR-494/G6pc axis drives glycogen and lipid droplet accumulation that favors cell survival under harsh conditions.","method":"Functional analysis, metabolic assays, live-imaging of HCC cells, qPCR in HCC patients and preclinical models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple metabolic assays and live-imaging with patient and preclinical data, single lab","pmids":["37301960"],"is_preprint":false},{"year":2019,"finding":"Glycerol can induce G6pc expression (a rate-limiting enzyme of gluconeogenesis) in primary mouse hepatocytes, demonstrating a substrate-level regulatory feedback on G6PC transcription. Glycerol is the preferred gluconeogenic substrate over pyruvate/lactate at physiological fasting concentrations both in vitro and in vivo.","method":"Primary mouse hepatocyte glucose production assays, 13C isotope tracing, real-time PCR for G6pc expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 13C isotope tracing plus gene expression measurement in primary hepatocytes and in vivo, single lab","pmids":["31645433"],"is_preprint":false},{"year":2025,"finding":"G6PC1 traffics to the plasma membrane via a CAV1 (Caveolin-1)-dependent vesicular pathway in hepatocytes. Liver-specific CAV1 knockout (L.Cav1-/- mice) reduced G6PC1 plasma membrane localization, decreased fasting hyperglycemia and hyperinsulinemia, and improved insulin sensitivity in mice on high-fat/high-sucrose diet, establishing that CAV1-mediated G6PC1 trafficking contributes to hepatic glucose production.","method":"Liver-specific CAV1 knockout mice (AAV or Cre-lox), glucose tolerance tests, fasting blood glucose and insulin measurements, in vivo glucose production assessment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KO with in vivo metabolic phenotyping, single lab, preprint not peer-reviewed","pmids":[],"is_preprint":true},{"year":2023,"finding":"G6PC1 and G6PC2 overexpression in 832/13 islet-derived cells blunted glucose-stimulated signaling (as measured by a transcriptional fusion gene assay), reflecting their role in reducing intraluminal G6P flux. However, G6PC1 and G6PC2 overexpression had minimal effect on glucocorticoid-stimulated HSD11B1 activity in either 832/13 or HepG2 cells, and G6pc2 knockout mice showed metabolic changes unaffected by G6PC2 absence, indicating G6PC1/G6PC2 activity does not significantly modulate HSD11B1-dependent glucocorticoid conversion.","method":"Transcriptional fusion gene assay, overexpression in 832/13 and HepG2 cells, G6pc2 knockout mice treated with 11-DHC","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines and in vivo KO with orthogonal assays, single lab","pmids":["37855366"],"is_preprint":false},{"year":2019,"finding":"Mice were generated with a conditional null allele for G6pc (loxP sites flanking Exon 3). EIIa-Cre-mediated deletion of Exon 3 produced a null phenotype mimicking G6Pase-alpha-deficient mice and human GSD-Ia, establishing that Exon 3 is essential for G6PC function in vivo.","method":"Conditional knockout mouse generation (loxP/Cre), phenotypic characterization","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined phenotypic readout, single lab","pmids":["19548314"],"is_preprint":false},{"year":2019,"finding":"Five novel G6PC1 mutations (p.V99Cfs*3, p.G125R, IVS1-2A>T, IVS3+39G>A, IVS3+42G>A) were identified in Indian GSD-1a patients. Functional characterization showed that mutant proteins p.G125R, p.R149Q, p.G118D, p.A331V, and p.V99Cfs*3 completely abrogated glucose-6-phosphatase activity without significant changes in mRNA or protein expression levels, indicating these residues are required for catalytic activity rather than protein stability.","method":"Direct DNA sequencing, glucose-6-phosphatase activity assay, RT-PCR and Western blot for expression","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay with expression controls, single lab, multiple variants","pmids":["30890478"],"is_preprint":false},{"year":2009,"finding":"In contrast to prevailing dogma, increased transcriptional expression of G6PC does not account for increased gluconeogenesis and fasting hyperglycemia in type 2 diabetes patients or in rodent models of fasting hyperglycemia (STZ/HFF rats and portal infusion models). Hepatic G6PC expression was not elevated in insulin-sensitive, insulin-resistant, or untreated T2DM patients undergoing bariatric surgery.","method":"Liver biopsy samples from human patients, rat models with portal vein infusion; mRNA quantification, endogenous glucose production measurement by isotope tracer","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human biopsy data plus two rodent models with isotope tracer measurements, single lab, result is a negative finding","pmids":["19587243"],"is_preprint":false}],"current_model":"G6PC1 (G6PC/G6Pase-alpha) is a nine-transmembrane-helix integral ER membrane protein that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the ER lumen via an induced-fit mechanism in which G6P binding drives conformational rearrangement of the catalytic pocket; it is transcriptionally regulated by ChREBP (via the Mediator kinase module/MED13) and FOXO1, post-transcriptionally regulated by METTL14-mediated m6A modification (read by YTHDF1/3 to enhance mRNA stability and translation) and by 3'-UTR ARE elements and miRNAs, and can traffic to the plasma membrane via a CAV1-dependent vesicular pathway; loss-of-function mutations that abolish enzymatic activity cause glycogen storage disease type Ia, while ≥3% residual hepatic activity is sufficient to prevent hepatocellular adenoma/carcinoma development."},"narrative":{"mechanistic_narrative":"G6PC1 (glucose-6-phosphatase-alpha) is an integral ER membrane glycoprotein that catalyzes the terminal, rate-limiting step of hepatic gluconeogenesis and glycogenolysis — hydrolysis of glucose-6-phosphate to glucose and phosphate — with its active center facing the ER lumen [PMID:18449899]. Cryo-EM structures resolve a nine-transmembrane-helix architecture with a large lumen-facing catalytic pocket, and show that substrate binding drives substantial conformational rearrangement of that pocket via an induced-fit mechanism, with phosphatidylserine implicated in regulating activity [PMID:40664655, PMID:39847333]. Extensive mutagenesis across the protein distinguishes residues required for catalysis from those required for protein stability and proper glycosylation/localization, and loss-of-function mutations that abolish enzymatic activity cause glycogen storage disease type Ia [PMID:10738525, PMID:18449899, PMID:30890478]. The enzyme's contribution to hepatic glucose production is dose-sensitive: restoring ≥3% of normal hepatic activity in G6pc-deficient mice prevents hepatocellular adenoma/carcinoma, linking G6Pase-alpha deficiency to impaired autophagy and hepatocarcinogenesis [PMID:32430177]. G6PC1 expression is controlled at multiple levels — transcriptionally through ChREBP and FOXO1 acting at the promoter, with the Mediator kinase subunit MED13 required for fructose-driven ChREBP-dependent activation, and antagonistically through RXRα at DR1 elements [PMID:33812059, PMID:37719384]; and post-transcriptionally through METTL14/METTL3-installed m6A marks read by YTHDF1/3 to enhance mRNA stability and translation, and through 3'-UTR AU-rich elements and miRNAs including miR-494 [PMID:40278833, PMID:28502559, PMID:37301960]. A CAV1-dependent vesicular pathway traffics G6PC1 to the plasma membrane to support hepatic glucose production.","teleology":[{"year":1999,"claim":"Established that specific G6PC residues are catalytically essential by showing defined missense mutations abolish enzymatic activity, moving GSD-Ia genotypes toward functional interpretation.","evidence":"Site-directed mutagenesis of four missense variants expressed in COS-7 cells with glucose-6-phosphatase activity assays","pmids":["10738525"],"confidence":"High","gaps":["Did not distinguish loss of catalysis from loss of folding/stability","No structural basis for residue importance"]},{"year":2008,"claim":"Consolidated the structure-function map of G6PC, defining it as an ER-membrane glycoprotein with a lumen-facing active center and classifying many mutations by their effect on activity versus stability.","evidence":"Compiled heterologous expression, enzymatic assays, and biochemical topology analysis across many mutations","pmids":["18449899"],"confidence":"High","gaps":["Topology and active-site geometry inferred biochemically, not from a structure","Regulatory inputs not addressed"]},{"year":2009,"claim":"Challenged the dogma that elevated G6PC transcription drives fasting hyperglycemia, showing hepatic G6PC mRNA is not increased in T2DM, reframing where dysregulation occurs.","evidence":"Human liver biopsies and rodent fasting-hyperglycemia models with mRNA quantification and isotope-tracer glucose production measurement","pmids":["19587243"],"confidence":"Medium","gaps":["Negative finding does not exclude post-transcriptional or trafficking-level regulation","Does not identify the actual driver of increased gluconeogenesis"]},{"year":2019,"claim":"Demonstrated in vivo dose-dependence of G6Pase-alpha activity by engineering a hyperactive variant, showing a threshold (≥3% activity) sufficient to prevent tumor development and linking deficiency to autophagy impairment.","evidence":"rAAV delivery of G6PC-S298C in G6pc-/- mice with hepatic activity assays and 66-week phenotyping","pmids":["32430177"],"confidence":"Medium","gaps":["Mechanism linking deficiency to autophagy impairment not fully defined","Single engineered variant in a mouse model"]},{"year":2019,"claim":"Provided a genetic tool and confirmed essentiality of G6pc Exon 3 in vivo, showing its deletion recapitulates human GSD-Ia.","evidence":"Conditional loxP/Cre knockout mouse with phenotypic characterization","pmids":["19548314"],"confidence":"Medium","gaps":["Phenotype establishes necessity but not tissue-specific regulatory detail"]},{"year":2019,"claim":"Identified substrate-level transcriptional feedback, showing glycerol — the preferred fasting gluconeogenic substrate — induces G6pc expression.","evidence":"Primary mouse hepatocyte glucose production assays, 13C isotope tracing, and qPCR","pmids":["31645433"],"confidence":"Medium","gaps":["Transcription factors mediating glycerol induction not identified","Physiological magnitude of feedback unclear"]},{"year":2021,"claim":"Placed G6pc transcription within the Mediator kinase module, showing MED13 is required for fructose-driven, ChREBP-dependent activation while FOXO1 promoter binding is independent of it.","evidence":"Liver-specific MED13 knockout mice with ChIP at the G6pc promoter, transcriptional activity assays, and glycogen measurements","pmids":["33812059"],"confidence":"High","gaps":["How MED13 couples to ChREBP at the promoter not resolved","Relative contribution of ChREBP vs FOXO1 not quantified"]},{"year":2021,"claim":"Refined variant pathogenicity interpretation by showing some VUS act through reduced protein levels, altered glycosylation, and mislocalization rather than catalysis alone.","evidence":"Heterologous fusion-protein expression of 29 variants with Western blot, glycosylation analysis, and immunofluorescence","pmids":["34258141"],"confidence":"Medium","gaps":["Enzymatic activity of all variants not directly measured","Single hepatocyte-derived cell line"]},{"year":2017,"claim":"Established post-transcriptional control of G6PC1 through the 3'-UTR, showing an ARE-dependent SNP destabilizes mRNA and sensitizes it to miRNA repression.","evidence":"Luciferase 3'-UTR reporter and miRNA reporter assays in HepG2 cells with deletion constructs","pmids":["28502559"],"confidence":"Medium","gaps":["Endogenous mRNA stability effect not measured","Specific trans-acting ARE-binding factors not identified"]},{"year":2023,"claim":"Identified RXRα-DR1 antagonism as a transcriptional brake, with retinaldehyde suppressing G6PC expression and glucose production.","evidence":"DR1 luciferase reporter assays, molecular docking, and mRNA/protein quantification in primary human hepatocytes and HepG2 cells","pmids":["37719384"],"confidence":"Medium","gaps":["In vivo physiological relevance not established","Endogenous occupancy of the DR1 element not directly shown"]},{"year":2023,"claim":"Linked G6pc repression to cancer metabolic rewiring, showing miR-494 represses G6pc to drive a glycolytic, glycogen/lipid-accumulating survival phenotype in hepatocellular carcinoma.","evidence":"Metabolic assays, live-imaging, and qPCR in HCC cells, patients, and preclinical models","pmids":["37301960"],"confidence":"Medium","gaps":["Direct miR-494/G6pc binding versus indirect effect not fully dissected","Mechanism connecting G6pc loss to HIF-1A activation incomplete"]},{"year":2023,"claim":"Clarified the functional scope of G6PC1/G6PC2 by showing they modulate intraluminal G6P flux and glucose-stimulated signaling but do not significantly drive HSD11B1-dependent glucocorticoid conversion.","evidence":"Transcriptional fusion gene assay and overexpression in 832/13 and HepG2 cells plus G6pc2 knockout mice","pmids":["37855366"],"confidence":"Medium","gaps":["Negative result for HSD11B1 coupling in specific systems only","G6PC1-specific (vs G6PC2) contribution to islet signaling not isolated"]},{"year":2025,"claim":"Defined the m6A regulatory layer, showing METTL14/METTL3 mark G6pc mRNA and YTHDF1/3 readers enhance its stability and translation to control hepatic glucose production.","evidence":"In vitro methylation, METTL14 KO/OE in hepatocytes and mice, five-site m6A mutagenesis (G6pcΔ5A), YTHDF RIP, mRNA stability and glucose production assays, and genetic rescue","pmids":["40278833"],"confidence":"High","gaps":["Upstream signals controlling METTL14 deposition on G6pc not defined","Why YTHDF2 does not bind not explained mechanistically"]},{"year":2025,"claim":"Resolved the long-inferred topology and catalytic mechanism at atomic resolution, showing nine TM helices, a lumen-facing pocket, an induced-fit substrate engagement, and a possible phosphatidylserine regulatory site.","evidence":"Cryo-EM of apo, fully-open, substrate (G6P/F6P)-bound, product-bound, and catalytic-mutant (H176A) states with functional analysis","pmids":["40664655","39847333"],"confidence":"High","gaps":["Catalytic chemistry of the phosphohydrolase step not fully detailed","Structural basis of phosphatidylserine regulation only partially defined"]},{"year":2025,"claim":"Extended G6PC1 function beyond the ER lumen, showing a CAV1-dependent vesicular pathway delivers it to the plasma membrane to contribute to hepatic glucose production.","evidence":"Liver-specific CAV1 knockout mice with glucose tolerance tests and fasting glucose/insulin measurements (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Functional role of plasma-membrane-localized G6PC1 versus ER-localized enzyme not resolved"]},{"year":null,"claim":"How the transcriptional (ChREBP/FOXO1/MED13/RXRα), m6A, 3'-UTR/miRNA, and CAV1-trafficking regulatory layers are integrated to set hepatic G6PC1 output under physiological fasting versus disease states remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking transcriptional, post-transcriptional, and trafficking control","Relative quantitative contribution of each regulatory layer in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,3,15]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,11,16]}],"complexes":[],"partners":["CAV1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35575","full_name":"Glucose-6-phosphatase catalytic subunit 1","aliases":["Glucose-6-phosphatase","G-6-Pase","G6Pase","Glucose-6-phosphatase alpha","G6Pase-alpha"],"length_aa":357,"mass_kda":40.5,"function":"Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. Forms with the glucose-6-phosphate transporter (SLC37A4/G6PT) the complex responsible for glucose production in the terminal step of glycogenolysis and gluconeogenesis. Hence, it is the key enzyme in homeostatic regulation of blood glucose levels","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P35575/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/G6PC1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/G6PC1","total_profiled":1310},"omim":[{"mim_id":"613742","title":"GLUCOSE-6-PHOSPHATASE, CATALYTIC SUBUNIT 1; G6PC1","url":"https://www.omim.org/entry/613742"},{"mim_id":"611045","title":"GLUCOSE-6-PHOSPHATASE, CATALYTIC SUBUNIT 3; G6PC3","url":"https://www.omim.org/entry/611045"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"kidney","ntpm":70.0},{"tissue":"liver","ntpm":253.6}],"url":"https://www.proteinatlas.org/search/G6PC1"},"hgnc":{"alias_symbol":["GSD1a"],"prev_symbol":["G6PT","G6PC"]},"alphafold":{"accession":"P35575","domains":[{"cath_id":"-","chopping":"2-351","consensus_level":"medium","plddt":93.6812,"start":2,"end":351}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35575","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35575-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35575-F1-predicted_aligned_error_v6.png","plddt_mean":92.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=G6PC1","jax_strain_url":"https://www.jax.org/strain/search?query=G6PC1"},"sequence":{"accession":"P35575","fasta_url":"https://rest.uniprot.org/uniprotkb/P35575.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35575/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35575"}},"corpus_meta":[{"pmid":"19587243","id":"PMC_19587243","title":"Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19587243","citation_count":133,"is_preprint":false},{"pmid":"18449899","id":"PMC_18449899","title":"Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease.","date":"2008","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/18449899","citation_count":124,"is_preprint":false},{"pmid":"20389290","id":"PMC_20389290","title":"Complete normalization of hepatic G6PC deficiency in murine glycogen storage disease type Ia using gene therapy.","date":"2010","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20389290","citation_count":69,"is_preprint":false},{"pmid":"29428299","id":"PMC_29428299","title":"G6PC mRNA Therapy Positively Regulates Fasting Blood Glucose and Decreases Liver Abnormalities in a Mouse Model of Glycogen Storage Disease 1a.","date":"2018","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29428299","citation_count":62,"is_preprint":false},{"pmid":"34216208","id":"PMC_34216208","title":"tRNA-derived fragment tRFLys-CTT-010 promotes triple-negative breast cancer progression by regulating glucose metabolism via G6PC.","date":"2021","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34216208","citation_count":36,"is_preprint":false},{"pmid":"37301960","id":"PMC_37301960","title":"MiR-494 induces metabolic changes through G6pc targeting and modulates sorafenib response in hepatocellular carcinoma.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37301960","citation_count":34,"is_preprint":false},{"pmid":"31645433","id":"PMC_31645433","title":"Glycerol induces G6pc in primary mouse hepatocytes and is the preferred substrate for gluconeogenesis both in vitro and in vivo.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31645433","citation_count":33,"is_preprint":false},{"pmid":"25926381","id":"PMC_25926381","title":"Genetic and molecular analyses reveal G6PC as a key element connecting glucose metabolism and cell cycle control in ovarian cancer.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25926381","citation_count":32,"is_preprint":false},{"pmid":"32567187","id":"PMC_32567187","title":"Large-scale transcriptome profiles reveal robust 20-signatures metabolic prediction models and novel role of G6PC in clear cell 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G6PC1 comprises nine transmembrane helices with a large catalytic pocket facing the ER lumen. Substrate binding induces substantial conformational rearrangements (induced-fit mechanism) in the catalytic pocket that facilitate sugar moiety binding. The structures also reveal a potential mechanism by which phosphatidylserine regulates G6PC1 activity.\",\n      \"method\": \"Cryo-EM structure determination with functional analysis; substrate-bound and apo forms resolved\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures in multiple states (apo, substrate-bound, product-bound) with functional validation in a single rigorous study\",\n      \"pmids\": [\"40664655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of wild-type human G6PC1 (apo) and a catalytic mutant G6PC1-H176A bound to G6P were solved, revealing nine transmembrane helices, a large catalytic pocket facing the ER lumen, and that G6P binding induces substantial conformational rearrangements in the catalytic pocket facilitating sugar moiety binding.\",\n      \"method\": \"Cryo-EM structure determination of wild-type apo and H176A mutant + G6P complex, with functional analyses\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM with active-site mutagenesis and substrate-bound structure in one rigorous study\",\n      \"pmids\": [\"39847333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Four missense mutations in G6PC (W77R, A124T, G184E, L211P) were individually introduced by site-directed mutagenesis and expressed in COS-7 cells; all four mutations completely abolished G6PC enzymatic (glucose-6-phosphatase) activity, establishing these residues as functionally critical.\",\n      \"method\": \"In vitro expression system (COS-7 cells), site-directed mutagenesis, enzymatic activity assay\",\n      \"journal\": \"Annals of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with active-site mutagenesis and enzymatic assay in a single focused study\",\n      \"pmids\": [\"10738525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"G6PC encodes glucose-6-phosphatase-alpha, a highly hydrophobic glycoprotein anchored in the ER membrane with its active center facing the ER lumen, catalyzing hydrolysis of glucose-6-phosphate to glucose and phosphate. Functional characterization of 50 missense, 2 nonsense, and 2 insertion/deletion mutations confirmed their effects on enzymatic activity and protein stability, establishing structure-function relationships across the protein.\",\n      \"method\": \"Compiled functional characterization from heterologous expression and enzymatic assays across multiple studies; topology established by biochemical analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic assays and mutagenesis replicated across many studies and summarized in this comprehensive review\",\n      \"pmids\": [\"18449899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A panel of 29 G6PC coding variants was heterologously expressed as fusion proteins in a hepatocyte-derived cell line. The screen revealed variant effects on steady-state protein levels, N-linked glycosylation status, and intracellular distribution. The VUS p.Cys109Tyr exhibited significantly reduced protein levels, altered glycosylation, and abnormally diffuse localization, consistent with pathogenicity.\",\n      \"method\": \"Heterologous expression of fusion proteins, Western blot for protein levels and glycosylation, immunofluorescence for intracellular distribution\",\n      \"journal\": \"JIMD reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (protein levels, glycosylation, localization) in a single lab study\",\n      \"pmids\": [\"34258141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A single amino acid substitution S298C in human G6PC (rAAV-G6PC-S298C) increased enzymatic efficacy approximately 3-fold compared to native G6PC in G6pc-/- mice, demonstrating that position 298 influences G6PC activity level in vivo. Restoring ≥3% of normal hepatic G6Pase-alpha activity prevented hepatocellular adenoma/carcinoma development, and G6Pase-alpha deficiency leads to hepatic autophagy impairment that can contribute to hepatocarcinogenesis.\",\n      \"method\": \"In vivo gene transfer in G6pc-/- mice, hepatic G6Pase activity assay, long-term (66-week) phenotypic characterization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo activity assay with engineered variant and long-term phenotypic readout, single lab\",\n      \"pmids\": [\"32430177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Mediator complex kinase module subunit MED13 is required for transcriptional activation of G6pc by fructose in the liver. In liver-specific MED13 knockout mice, ChREBP binding to the G6pc promoter was dramatically reduced and ChREBP-beta and FOXO1 transcriptional activities were suppressed, while FOXO1 binding to the G6pc promoter was unaffected. This establishes that MED13/Mediator kinase module is necessary for ChREBP-dependent G6pc transcription and consequent regulation of liver glycogen levels.\",\n      \"method\": \"Liver-specific MED13 knockout mice, G6PC enzymatic activity assay, ChIP assay at G6pc promoter, transcriptional activity assays in hepatocytes, glycogen measurements\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with ChIP and enzymatic assays, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"33812059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL14, in complex with METTL3, installs N6-methyladenosine (m6A) on G6pc mRNA at five sites. m6A readers YTHDF1 and YTHDF3 (but not YTHDF2) bind to m6A-marked G6pc mRNA to increase both its stability and translation, thereby increasing G6PC protein levels and hepatic glucose production. Deletion of five m6A sites (G6pcΔ5A) blocked METTL14-induced effects. Liver-specific Mettl14 knockout decreased G6pc expression and gluconeogenesis; hepatocyte-specific G6pc restoration reversed defective hepatic glucose production in Mettl14 KO mice.\",\n      \"method\": \"In vitro m6A methylation, METTL14 KO and OE in hepatocytes and mice, m6A site mutagenesis (G6pcΔ5A), RIP assays, mRNA stability assay, glucose production assay, genetic rescue experiment\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (m6A mutagenesis, YTHDF RIP, KO + rescue, in vitro and in vivo) in a single rigorous study\",\n      \"pmids\": [\"40278833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A 3'-UTR SNP rs2229611 in G6PC1 reduces mRNA stability and decreases expression. In HepG2 cells, luciferase constructs bearing the rs2229611 allele showed significantly decreased expression compared to wild-type 3'-UTR, due to reduced mRNA stability mediated by AU-rich elements (AREs). miRNAs also showed more distinct inhibition of reporter function with rs2229611. This demonstrates a post-transcriptional regulatory mechanism for G6PC1 expression.\",\n      \"method\": \"Luciferase reporter assay in HepG2 cells, 3'-UTR deletion constructs, pmirGLO-UTR constructs for miRNA effects\",\n      \"journal\": \"Clinica chimica acta; international journal of clinical chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple reporter constructs with orthogonal approaches (deletion series, miRNA reporters) in single lab\",\n      \"pmids\": [\"28502559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Retinaldehyde (Rald) downregulates G6PC expression by antagonizing retinoid X receptor alpha (RXRα) at direct repeat 1 (DR1) response elements in the G6PC/PCK1 promoters. This was confirmed by luciferase reporter assays and molecular docking. In primary human hepatocytes and HepG2 cells, Rald treatment decreased G6PC mRNA and protein expression and reduced glucose production.\",\n      \"method\": \"Luciferase reporter assays (DR1 elements), molecular docking, primary human hepatocyte experiments, mRNA/protein quantification\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, docking, primary human hepatocytes) in single lab\",\n      \"pmids\": [\"37719384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-494 targets G6pc mRNA in hepatocellular carcinoma cells, inducing a metabolic shift toward glycolytic phenotype through G6pc repression and HIF-1A pathway activation. The miR-494/G6pc axis drives glycogen and lipid droplet accumulation that favors cell survival under harsh conditions.\",\n      \"method\": \"Functional analysis, metabolic assays, live-imaging of HCC cells, qPCR in HCC patients and preclinical models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple metabolic assays and live-imaging with patient and preclinical data, single lab\",\n      \"pmids\": [\"37301960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Glycerol can induce G6pc expression (a rate-limiting enzyme of gluconeogenesis) in primary mouse hepatocytes, demonstrating a substrate-level regulatory feedback on G6PC transcription. Glycerol is the preferred gluconeogenic substrate over pyruvate/lactate at physiological fasting concentrations both in vitro and in vivo.\",\n      \"method\": \"Primary mouse hepatocyte glucose production assays, 13C isotope tracing, real-time PCR for G6pc expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 13C isotope tracing plus gene expression measurement in primary hepatocytes and in vivo, single lab\",\n      \"pmids\": [\"31645433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"G6PC1 traffics to the plasma membrane via a CAV1 (Caveolin-1)-dependent vesicular pathway in hepatocytes. Liver-specific CAV1 knockout (L.Cav1-/- mice) reduced G6PC1 plasma membrane localization, decreased fasting hyperglycemia and hyperinsulinemia, and improved insulin sensitivity in mice on high-fat/high-sucrose diet, establishing that CAV1-mediated G6PC1 trafficking contributes to hepatic glucose production.\",\n      \"method\": \"Liver-specific CAV1 knockout mice (AAV or Cre-lox), glucose tolerance tests, fasting blood glucose and insulin measurements, in vivo glucose production assessment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KO with in vivo metabolic phenotyping, single lab, preprint not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"G6PC1 and G6PC2 overexpression in 832/13 islet-derived cells blunted glucose-stimulated signaling (as measured by a transcriptional fusion gene assay), reflecting their role in reducing intraluminal G6P flux. However, G6PC1 and G6PC2 overexpression had minimal effect on glucocorticoid-stimulated HSD11B1 activity in either 832/13 or HepG2 cells, and G6pc2 knockout mice showed metabolic changes unaffected by G6PC2 absence, indicating G6PC1/G6PC2 activity does not significantly modulate HSD11B1-dependent glucocorticoid conversion.\",\n      \"method\": \"Transcriptional fusion gene assay, overexpression in 832/13 and HepG2 cells, G6pc2 knockout mice treated with 11-DHC\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines and in vivo KO with orthogonal assays, single lab\",\n      \"pmids\": [\"37855366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mice were generated with a conditional null allele for G6pc (loxP sites flanking Exon 3). EIIa-Cre-mediated deletion of Exon 3 produced a null phenotype mimicking G6Pase-alpha-deficient mice and human GSD-Ia, establishing that Exon 3 is essential for G6PC function in vivo.\",\n      \"method\": \"Conditional knockout mouse generation (loxP/Cre), phenotypic characterization\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined phenotypic readout, single lab\",\n      \"pmids\": [\"19548314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Five novel G6PC1 mutations (p.V99Cfs*3, p.G125R, IVS1-2A>T, IVS3+39G>A, IVS3+42G>A) were identified in Indian GSD-1a patients. Functional characterization showed that mutant proteins p.G125R, p.R149Q, p.G118D, p.A331V, and p.V99Cfs*3 completely abrogated glucose-6-phosphatase activity without significant changes in mRNA or protein expression levels, indicating these residues are required for catalytic activity rather than protein stability.\",\n      \"method\": \"Direct DNA sequencing, glucose-6-phosphatase activity assay, RT-PCR and Western blot for expression\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay with expression controls, single lab, multiple variants\",\n      \"pmids\": [\"30890478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In contrast to prevailing dogma, increased transcriptional expression of G6PC does not account for increased gluconeogenesis and fasting hyperglycemia in type 2 diabetes patients or in rodent models of fasting hyperglycemia (STZ/HFF rats and portal infusion models). Hepatic G6PC expression was not elevated in insulin-sensitive, insulin-resistant, or untreated T2DM patients undergoing bariatric surgery.\",\n      \"method\": \"Liver biopsy samples from human patients, rat models with portal vein infusion; mRNA quantification, endogenous glucose production measurement by isotope tracer\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human biopsy data plus two rodent models with isotope tracer measurements, single lab, result is a negative finding\",\n      \"pmids\": [\"19587243\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"G6PC1 (G6PC/G6Pase-alpha) is a nine-transmembrane-helix integral ER membrane protein that catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the ER lumen via an induced-fit mechanism in which G6P binding drives conformational rearrangement of the catalytic pocket; it is transcriptionally regulated by ChREBP (via the Mediator kinase module/MED13) and FOXO1, post-transcriptionally regulated by METTL14-mediated m6A modification (read by YTHDF1/3 to enhance mRNA stability and translation) and by 3'-UTR ARE elements and miRNAs, and can traffic to the plasma membrane via a CAV1-dependent vesicular pathway; loss-of-function mutations that abolish enzymatic activity cause glycogen storage disease type Ia, while ≥3% residual hepatic activity is sufficient to prevent hepatocellular adenoma/carcinoma development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"G6PC1 (glucose-6-phosphatase-alpha) is an integral ER membrane glycoprotein that catalyzes the terminal, rate-limiting step of hepatic gluconeogenesis and glycogenolysis — hydrolysis of glucose-6-phosphate to glucose and phosphate — with its active center facing the ER lumen [#3]. Cryo-EM structures resolve a nine-transmembrane-helix architecture with a large lumen-facing catalytic pocket, and show that substrate binding drives substantial conformational rearrangement of that pocket via an induced-fit mechanism, with phosphatidylserine implicated in regulating activity [#0, #1]. Extensive mutagenesis across the protein distinguishes residues required for catalysis from those required for protein stability and proper glycosylation/localization, and loss-of-function mutations that abolish enzymatic activity cause glycogen storage disease type Ia [#2, #3, #15]. The enzyme's contribution to hepatic glucose production is dose-sensitive: restoring \\u22653% of normal hepatic activity in G6pc-deficient mice prevents hepatocellular adenoma/carcinoma, linking G6Pase-alpha deficiency to impaired autophagy and hepatocarcinogenesis [#5]. G6PC1 expression is controlled at multiple levels — transcriptionally through ChREBP and FOXO1 acting at the promoter, with the Mediator kinase subunit MED13 required for fructose-driven ChREBP-dependent activation, and antagonistically through RXR\\u03b1 at DR1 elements [#6, #9]; and post-transcriptionally through METTL14/METTL3-installed m6A marks read by YTHDF1/3 to enhance mRNA stability and translation, and through 3'-UTR AU-rich elements and miRNAs including miR-494 [#7, #8, #10]. A CAV1-dependent vesicular pathway traffics G6PC1 to the plasma membrane to support hepatic glucose production [#12].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that specific G6PC residues are catalytically essential by showing defined missense mutations abolish enzymatic activity, moving GSD-Ia genotypes toward functional interpretation.\",\n      \"evidence\": \"Site-directed mutagenesis of four missense variants expressed in COS-7 cells with glucose-6-phosphatase activity assays\",\n      \"pmids\": [\"10738525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish loss of catalysis from loss of folding/stability\", \"No structural basis for residue importance\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Consolidated the structure-function map of G6PC, defining it as an ER-membrane glycoprotein with a lumen-facing active center and classifying many mutations by their effect on activity versus stability.\",\n      \"evidence\": \"Compiled heterologous expression, enzymatic assays, and biochemical topology analysis across many mutations\",\n      \"pmids\": [\"18449899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Topology and active-site geometry inferred biochemically, not from a structure\", \"Regulatory inputs not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Challenged the dogma that elevated G6PC transcription drives fasting hyperglycemia, showing hepatic G6PC mRNA is not increased in T2DM, reframing where dysregulation occurs.\",\n      \"evidence\": \"Human liver biopsies and rodent fasting-hyperglycemia models with mRNA quantification and isotope-tracer glucose production measurement\",\n      \"pmids\": [\"19587243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative finding does not exclude post-transcriptional or trafficking-level regulation\", \"Does not identify the actual driver of increased gluconeogenesis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated in vivo dose-dependence of G6Pase-alpha activity by engineering a hyperactive variant, showing a threshold (\\u22653% activity) sufficient to prevent tumor development and linking deficiency to autophagy impairment.\",\n      \"evidence\": \"rAAV delivery of G6PC-S298C in G6pc-/- mice with hepatic activity assays and 66-week phenotyping\",\n      \"pmids\": [\"32430177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking deficiency to autophagy impairment not fully defined\", \"Single engineered variant in a mouse model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided a genetic tool and confirmed essentiality of G6pc Exon 3 in vivo, showing its deletion recapitulates human GSD-Ia.\",\n      \"evidence\": \"Conditional loxP/Cre knockout mouse with phenotypic characterization\",\n      \"pmids\": [\"19548314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phenotype establishes necessity but not tissue-specific regulatory detail\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified substrate-level transcriptional feedback, showing glycerol — the preferred fasting gluconeogenic substrate — induces G6pc expression.\",\n      \"evidence\": \"Primary mouse hepatocyte glucose production assays, 13C isotope tracing, and qPCR\",\n      \"pmids\": [\"31645433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors mediating glycerol induction not identified\", \"Physiological magnitude of feedback unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed G6pc transcription within the Mediator kinase module, showing MED13 is required for fructose-driven, ChREBP-dependent activation while FOXO1 promoter binding is independent of it.\",\n      \"evidence\": \"Liver-specific MED13 knockout mice with ChIP at the G6pc promoter, transcriptional activity assays, and glycogen measurements\",\n      \"pmids\": [\"33812059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MED13 couples to ChREBP at the promoter not resolved\", \"Relative contribution of ChREBP vs FOXO1 not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined variant pathogenicity interpretation by showing some VUS act through reduced protein levels, altered glycosylation, and mislocalization rather than catalysis alone.\",\n      \"evidence\": \"Heterologous fusion-protein expression of 29 variants with Western blot, glycosylation analysis, and immunofluorescence\",\n      \"pmids\": [\"34258141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic activity of all variants not directly measured\", \"Single hepatocyte-derived cell line\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established post-transcriptional control of G6PC1 through the 3'-UTR, showing an ARE-dependent SNP destabilizes mRNA and sensitizes it to miRNA repression.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter and miRNA reporter assays in HepG2 cells with deletion constructs\",\n      \"pmids\": [\"28502559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous mRNA stability effect not measured\", \"Specific trans-acting ARE-binding factors not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified RXR\\u03b1-DR1 antagonism as a transcriptional brake, with retinaldehyde suppressing G6PC expression and glucose production.\",\n      \"evidence\": \"DR1 luciferase reporter assays, molecular docking, and mRNA/protein quantification in primary human hepatocytes and HepG2 cells\",\n      \"pmids\": [\"37719384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo physiological relevance not established\", \"Endogenous occupancy of the DR1 element not directly shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked G6pc repression to cancer metabolic rewiring, showing miR-494 represses G6pc to drive a glycolytic, glycogen/lipid-accumulating survival phenotype in hepatocellular carcinoma.\",\n      \"evidence\": \"Metabolic assays, live-imaging, and qPCR in HCC cells, patients, and preclinical models\",\n      \"pmids\": [\"37301960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-494/G6pc binding versus indirect effect not fully dissected\", \"Mechanism connecting G6pc loss to HIF-1A activation incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Clarified the functional scope of G6PC1/G6PC2 by showing they modulate intraluminal G6P flux and glucose-stimulated signaling but do not significantly drive HSD11B1-dependent glucocorticoid conversion.\",\n      \"evidence\": \"Transcriptional fusion gene assay and overexpression in 832/13 and HepG2 cells plus G6pc2 knockout mice\",\n      \"pmids\": [\"37855366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result for HSD11B1 coupling in specific systems only\", \"G6PC1-specific (vs G6PC2) contribution to islet signaling not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the m6A regulatory layer, showing METTL14/METTL3 mark G6pc mRNA and YTHDF1/3 readers enhance its stability and translation to control hepatic glucose production.\",\n      \"evidence\": \"In vitro methylation, METTL14 KO/OE in hepatocytes and mice, five-site m6A mutagenesis (G6pc\\u03945A), YTHDF RIP, mRNA stability and glucose production assays, and genetic rescue\",\n      \"pmids\": [\"40278833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling METTL14 deposition on G6pc not defined\", \"Why YTHDF2 does not bind not explained mechanistically\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the long-inferred topology and catalytic mechanism at atomic resolution, showing nine TM helices, a lumen-facing pocket, an induced-fit substrate engagement, and a possible phosphatidylserine regulatory site.\",\n      \"evidence\": \"Cryo-EM of apo, fully-open, substrate (G6P/F6P)-bound, product-bound, and catalytic-mutant (H176A) states with functional analysis\",\n      \"pmids\": [\"40664655\", \"39847333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic chemistry of the phosphohydrolase step not fully detailed\", \"Structural basis of phosphatidylserine regulation only partially defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended G6PC1 function beyond the ER lumen, showing a CAV1-dependent vesicular pathway delivers it to the plasma membrane to contribute to hepatic glucose production.\",\n      \"evidence\": \"Liver-specific CAV1 knockout mice with glucose tolerance tests and fasting glucose/insulin measurements (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Functional role of plasma-membrane-localized G6PC1 versus ER-localized enzyme not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the transcriptional (ChREBP/FOXO1/MED13/RXR\\u03b1), m6A, 3'-UTR/miRNA, and CAV1-trafficking regulatory layers are integrated to set hepatic G6PC1 output under physiological fasting versus disease states remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking transcriptional, post-transcriptional, and trafficking control\", \"Relative quantitative contribution of each regulatory layer in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 3, 15]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 11, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CAV1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}