G6PC1

Summary: The disease-associated G188R study is consistent with the established catalytic function.

Reason: The authentic PMID:10960498 abstract describes the human G188R disease variant and clinical/genetic findings but does not expose all functional methods. The existing EXP assertion is retained because glucose-6-phosphatase activity of human G6PC1 is independently demonstrated. That abstract does not establish a mutant-expression assay or activity of both current natural products.

Summary: Human wild-type and active-site experiments directly demonstrate glucose-6-phosphate hydrolysis.

Reason: The original PMID:12093795 Methods and Results assay human G6PC1 expressed in COS-1 or adenovirus-infected CRE8 cells, with expression controls and active-site mutants. Wild type releases inorganic phosphate from glucose-6-phosphate; key active-site substitutions abolish activity. Tagged constructs and a covalent phosphohistidine intermediate are experimental details, not separate natural isoforms.

Summary: Human T16R and Y209C experiments support the catalytic role and variant-dependent loss of activity.

Reason: The authentic PMID:15542400 abstract explicitly reports that the two human variants lose glucose-6-phosphatase activity and have reduced stability in a transient-expression assay. This supports the wild-type molecular function while distinguishing disease-associated loss of activity from a negated wild-type assertion. Full quantitative methods and exact modern isoform assignment were not recovered.

Summary: The human V166G disease-variant expression experiment supports the phosphatase function.

Reason: The authentic PMID:9332655 abstract describes expression of human wild-type and V166G G6PC1 in COS-1 cells and loss of enzymatic activity for the variant. Preserve the human protein versus heterologous host distinction. The experiment does not demonstrate that every alternatively spliced product has equivalent activity.

Summary: Topology and active-site mutagenesis support the human G6PC1 catalytic function.

Reason: PMID:9497333 provides the earlier human topology and active-site study, consistent with the phosphatase function. Its prediction of the catalytic phosphate-accepting residue is distinguished from the later direct covalent-intermediate identification in PMID:12093795 and structural work in PMID:39847333. Neither topology predictions nor disease variants are treated as new natural products.

Summary: The inherited glucose-6-phosphatase activity is the established catalytic function of G6PC1.

Reason: The actual PTHR12591 tree places human P35575 at AN15/PTN002488968 below the asserted AN0/PTN000971890 origin. The full 357-residue canonical sequence matches the family alignment, and the literal descendant-evidence set agrees with the retained IBD record. Human catalytic experiments identify glucose-6-phosphate hydrolysis and its phosphohistidine intermediate, independently supporting this activity. The target appearing among the IBD descendant evidence is legitimate experimental grounding, not circular support. No target-specific loss or placement defect was found. This assessment does not transfer activity to the separately declared 176-residue product.

Summary: The curated human enzyme-activity assertion agrees with independent direct G6PC1 biochemistry.

Reason: The accessible PMID:10318794 abstract foregrounds the glucose-6-phosphate transporter. This does not establish that the full paper omitted the catalytic subunit. Preserve the curated G6PC1 IDA and defer to the original curator for the exact assay context; the function itself is directly supported by human G6PC1 studies. No transporter activity is assigned to the phosphatase.

Summary: The imported activity agrees with direct G6PC1 evidence despite the paralog focus of the accessible abstract.

Reason: PMID:15661744 foregrounds G6PC3 in the authentic abstract. The full experiment may include G6PC1 comparisons, and an abstract title is insufficient to reject a curator-read IDA. Retain the independently established G6PC1 catalytic function without claiming that the foregrounded astrocyte/paralog results are human G6PC1-specific experiments.

Summary: Human G6PC1 cloning and expression establish the glucose-6-phosphatase catalytic function.

Reason: The authentic PMID:8211187 abstract reports human gene cloning/expression and disease-causing variants that inactivate the enzyme. This directly supports the human catalytic activity and links its loss to glucose-production failure. It is not source-specific evidence for the separate drug, hormone or nutrient-response annotations.

Summary: The combined electronic sources agree with the experimentally established glucose-6-phosphatase activity.

Reason: The unchanged combined annotation retains its mouse and rat donor identifiers, ARBA rule, InterPro signature, RHEA reaction and EC mapping. Human cloning/expression, active-site experiments and purified human G6PC1 hydrolysis independently establish the same activity. These multiple electronic mappings are not counted as independent experiments, and no complete ARBA condition audit is claimed.

Summary: The disease reaction records loss of the normal G6PC1 phosphatase activity.

Reason: The official R-HSA-3274540 entry models defective G6PC variants and explicitly identifies their normal counterpart as the glucose-6-phosphate hydrolysis reaction. Retain glucose-6-phosphatase activity for the unqualified wild-type gene product, with independent direct human evidence. The modeled loss-of-function mutants are not evidence that those mutant proteins retain the activity, and are not natural isoforms.

Summary: A positive human G6PC1–WFS1 two-hybrid association is independently present in the original network table.

Reason: Original PMID:32814053 Table S2, sheet NN1.0, Excel row 12842 lists G6PC (Entrez 2538) with WFS1 (7466). The exact IntAct P35575–O76024 records report human participants tested in yeast, with pooling, array and validated two-hybrid annotations; these are stages of the same screening system rather than three independent physiological assays. The paper screened full-length cDNAs and fragments and retested candidate pairs after excluding autoactivating baits. The exact G6PC1/WFS1 construct boundaries are not independently resolved here, and blank IntAct feature fields are not evidence of full-length constructs. No G6PC pair was found in the inspected DULIP workbook; that absence is not a negative binding result. Retain the positive generic association under the standing campaign policy, without inferring an endogenous complex, altered catalytic activity or a new pathway role.

Summary: A positive human G6PC1–RNF11 two-hybrid association is independently present in the original network table.

Reason: Original PMID:32814053 Table S2, sheet NN1.0, Excel row 9030 lists G6PC (Entrez 2538) with RNF11 (26994). Exact IntAct P35575–Q9Y3C5 records identify human participants in a yeast host and positive pooling, array and validated two-hybrid stages. The original Methods describe reporter-based selection after bait autoactivation exclusion and pairwise retesting; these related stages do not independently establish a cellular regulatory mechanism. Exact construct boundaries and a mammalian G6PC1–RNF11 validation are unresolved in the inspected sources. The paper’s DULIP subset contains no G6PC row, which must not be treated as a negative result. Preserve the measured association as non-core under the standing binding policy; do not infer RNF11-dependent ubiquitination of G6PC1 or an endogenous complex from this screen.

Summary: The endoplasmic reticulum is a supported core location, with the membrane sub-compartment retained separately.

Reason: The actual PTHR12591 tree and literal IBD record place the human target below the endoplasmic-reticulum origin AN0/PTN000971890. Independent human topology and structural evidence places the catalytic protein in the ER membrane with the catalytic center facing the lumen. This supports the organelle-level assertion as well as the separately retained ER-membrane annotation. Under the established organelle policy the informative root location is not TOO_GENERAL merely because its sub-compartment is known. No inference is made from the GOA relationship qualifier.

Summary: G6PC1 is an endoplasmic-reticulum enzyme, consistent with the reviewed orthology inference.

Reason: This Ensembl assertion transfers the ER location from mouse G6pc1 (P35576; ENSMUSP00000019469), the established ortholog. The mouse microsomal enzyme and the independently characterized human integral ER-membrane protein support the organelle claim; human topology and structure place its catalytic site toward the ER lumen. The ER-membrane annotation supplies additional compartment detail without invalidating the organelle-level assertion. The explicit ORGANELLES policy retains supported root-organelle assertions after examining their source; no localization loss or divergence is indicated.

Summary: The UniProt subcellular-location mapping correctly identifies the endoplasmic-reticulum membrane.

Reason: The unchanged SL-0097 mapping agrees with human G6PC1 topology and modern structure. Canonical G6PC1 contains nine transmembrane helices with its catalytic pocket facing the ER lumen. The luminal active site does not mean the whole integral membrane protein is a freely soluble luminal enzyme, and activity/topology are not automatically assigned to the 176-residue alternate product.

Summary: Human topology experiments support G6PC1 as an endoplasmic-reticulum membrane protein.

Reason: The authentic PMID:9497333 source reports the nine-transmembrane topology and luminal catalytic organization, subsequently supported structurally. This supports the existing ER-membrane location without upgrading the original NAS evidence code or equating engineered topology constructs with naturally spliced products.

Summary: The imported ER-membrane location agrees with independent human G6PC1 topology.

Reason: Although the accessible PMID:10318794 abstract emphasizes the associated transporter, it does not invalidate the curator's G6PC1 membrane-location assertion. Direct human topology and structural sources independently place the catalytic protein in the ER membrane. Keep the original TAS provenance and distinguish transport of substrate by G6PT from hydrolysis by G6PC1.

Summary: The disease model retains the ER-membrane compartment of the G6PC1 protein.

Reason: R-HSA-3274540 explicitly places G6PC mutants and their normal counterpart in the ER membrane. The location is independently supported for canonical human G6PC1. The model's loss of catalytic function is distinguished from a global loss of membrane localization; individual mutant trafficking behavior is not generalized.

Summary: The normal hepatic reaction explicitly places G6PC1 in the ER membrane.

Reason: R-HSA-71825 describes membrane-associated G6PC1 catalyzing glucose-6-phosphate hydrolysis on the luminal side. This matches direct human topology and structure. The existing compartment assertion is retained without assigning the separate substrate-transport activity to G6PC1.

Summary: The official Reactome participant display places the G6PC protein output in the ER membrane.

Reason: The official external participant display for R-HSA-9944724 identifies a nucleoplasmic G6PC gene input and an ER-membrane G6PC protein output. The cached event summary describes TCF19/NuRD-mediated repression but does not contain that participant compartment. The protein location is independently supported by human G6PC1 structure. Retaining this location does not assign NuRD chromatin regulation, nuclear localization or repression of its own gene to the G6PC1 enzyme.

Summary: G6PC1 performs the terminal hydrolytic step enabling glucose release from glycogen-derived glucose-6-phosphate.

Reason: Human G6PC1 hydrolyzes glucose-6-phosphate at the terminal glucose-release step downstream of hepatic glycogen breakdown. PMID:9332655 explicitly identifies this as the final common step of glycogenolysis and gluconeogenesis, and human structural/biochemical evidence establishes the hydrolysis. The existing glycogen-metabolic-process annotation is retained as pathway-level participation in this catabolic branch, not glycogen synthesis or direct cleavage of the glycogen polymer. The broad existing assertion is represented explicitly in the core synthesis; no additional or replacement glycogen annotation is introduced.

Summary: G6PC1 performs the terminal glucose-releasing step of gluconeogenesis.

Reason: Human G6PC1 catalyzes glucose-6-phosphate hydrolysis, supplying glucose at the terminal step of gluconeogenesis. The actual family places the exact human canonical target AN15/PTN002488968 beneath the gluconeogenesis IBD at AN0/PTN000971890, with the incoming literal descendant-evidence set recovered unchanged. The presence of the human target within that set is valid experimental grounding, and no sequence or topology evidence contradicts inheritance of this role by G6PC1. This accepts the target’s participation; it does not assert identical tissue physiology or gluconeogenic contributions for every paralog elsewhere in the ancestral clade.

Summary: The combined electronic gluconeogenesis annotation agrees with the directly established terminal enzymatic step.

Reason: The original ARBA, UniPathway and mouse/rat orthology sources remain distinct provenance for this combined assertion. G6PC1 hydrolyzes the glucose-6-phosphate produced by gluconeogenesis to free glucose, providing direct biochemical participation. Independent human catalytic and pathway evidence supports the process; this does not imply that every electronic source was newly curated or independently experimentally tested.

Summary: Human loss-of-function evidence and the demonstrated catalytic step support gluconeogenesis.

Reason: The human cloning and disease-mutation findings in PMID:8211187 connect loss of G6PC1 enzyme activity to deficient glucose production. The process assignment is also anchored to the enzyme performing the terminal glucose-6-phosphate hydrolysis step, rather than necessity inferred solely from a disease phenotype. Preserve the original IMP provenance.

Summary: The gluconeogenesis pathway is supported by G6PC1-mediated terminal glucose production.

Reason: R-HSA-70263 describes glucose synthesis through glucose-6-phosphate; the explicit normal G6PC reaction R-HSA-71825 supplies its hydrolysis to glucose at the ER. G6PC1 is the catalyst of that step. No mitochondrial pyruvate-carboxylation, phosphoenolpyruvate synthesis or other enzymes' activities are transferred from the pathway overview to G6PC1.

Summary: Rat carbohydrate-infusion experiments support a non-core expression response to carbohydrate.

Reason: The unchanged transfer donor is rat P43428/ENSRNOP00000071453. The authentic abstract of PMID:14988444 reports hepatic G6pc mRNA responses during glucose or glucose-plus-fructose infusion in rats under pancreatic clamps. At equal total hepatic sugar load, the low- and high-fructose conditions produce different expression responses, providing positive support for the carbohydrate-response term, whose definition includes gene-expression changes. This is ortholog-supported nutritional regulation, not a direct carbohydrate-sensing activity of human G6PC1. The separate PMID:26883980 donor annotation retains its original provenance, but its abstract does not resolve the exact carbohydrate-stimulus experiment; that limitation does not negate the independent infusion evidence.

Summary: The generic membrane location is subsumed by the established ER-membrane location.

Reason: The membrane IBD at AN0/PTN000971890 is valid for the exact human target, and its sole human descendant evidence is legitimate rather than circular. Its broad membrane claim is correct. The review already retains endoplasmic reticulum membrane, which is the specific location supported by human topology and catalytic mechanism. Official typed edges place ER membrane is_a organelle membrane is_a membrane. TOO_GENERAL therefore records gene-level granularity, without disputing the ancestral placement or its evidence. The separate organelle-root retention policy applies to endoplasmic reticulum, not to the nonspecific membrane category.

Summary: The membrane assertion is represented more precisely by endoplasmic-reticulum membrane.

Reason: The original IDA membrane annotation is compatible with G6PC1 biology. Direct topology/structure and explicit reaction modeling identify the specific ER membrane compartment, which is a typed descendant of membrane. TOO_GENERAL records this redundant breadth rather than disputing the experimental assertion or inferring a wrong-gene citation from the transporter-focused abstract.

Summary: Measured mouse phosphotransferase activity is real, but its physiological use by G6PC1 is unestablished.

Reason: The unchanged donor is mouse P35576/ENSMUSP00000019469. PMID:8407995 Methods, Table I and Results report glucose-6-phosphate formation from glucose and carbamyl phosphate in disrupted microsomes expressing cloned mouse G6pc, with mock controls. This supports the measured phosphotransferase capability and is not contradicted by the enzyme's hydrolase classification. The experiment does not establish use of this reaction in intact cells or a physiological secondary role for human G6PC1. Under the measured-activity policy, the functional annotation therefore exceeds the demonstrated relevance and is MARK_AS_OVER_ANNOTATED. This judgment does not deny the positive assay, label it noise, or treat the assay as direct reversal of the essentially irreversible G6P hydrolysis reaction.

Summary: The supported food-response context supplies the more specific nutrient-response coverage.

Reason: The literal rat nutrient-response donor cites PMID:25943649; its abstract does not expose the G6pc-specific measurement, so no assay detail is invented. Independently, the retained food-response annotation is supported by rat dietary/amino-acid and fructose experiments. Official typed GO ancestry places response to food under response to nutrient levels, making the broader process redundant within this review. This is a specificity decision, not a claim that the original donor experiment is invalid.

Summary: Rat dietary perturbations support non-core expression responses to food-related stimuli.

Reason: The exact rat donor has IEP records from PMID:14988444 and PMID:17158265. Their authentic abstracts report changes in hepatic G6pc expression under controlled fructose concentrations and high-protein/amino-acid conditions, respectively. These are positive expression-response observations under the GO definition, not evidence that G6PC1 senses food directly or that a particular regulatory direction applies in every tissue or species.

Summary: The insulin-response category is represented more specifically by the existing cellular response term.

Reason: The rat donor PMID:27366200 measures hepatic G6pc expression in diabetic rats treated with insulin with or without adjunct resveratrol. Its Results do not simply show universal insulin suppression; the insulin-treated group differs from non-diabetic controls and adjunct resveratrol lowers expression. The independently supported cellular response to insulin term is a typed descendant of response to insulin and already captures the narrower response category.

Summary: The donor promoter experiment supports a non-core cellular response to insulin.

Reason: The exact rat donor IEP points to PMID:19579180. The authentic abstract reports inhibition of basal and dexamethasone/cAMP-stimulated G6Pase promoter activity by insulin in hepatoma cells, with condition-dependent AMPK-inhibitor effects. This supports an expression response, not G6PC1 receptor signaling, direct insulin binding or a claim that G6PC1 itself is AMPK. Full construct-level methods were not recovered and no cell-line identity beyond the abstract is invented.

Summary: Noncovalent contacts with substrate-bound phosphate are established; the exact phosphate-ion binding assertion remains unresolved.

Reason: PMID:39847333 directly resolves noncovalent contacts between Lys76, Arg83, Arg170 and Ser117 and the phosphate group of glucose-6-phosphate in the engineered human H176A substrate-trapping structure. In the apo structure, Glu110 occupies the corresponding electrostatic environment and is proposed as a phosphate surrogate. These observations establish recognition of the phosphate moiety of a phosphomonoester; they do not by themselves establish binding of a separate inorganic phosphate ion. The original PMID:12093795 experiment instead identifies a covalent His176 phosphoenzyme intermediate. GO:0042301 names phosphate-ion binding and its binding parent requires a noncovalent interaction. UNDECIDED therefore concerns whether the demonstrated ester-bound phosphate contacts support this exact ligand assertion, not inaccessible evidence or doubt about substrate recognition. The original IMP provenance is retained without asserting a false annotation.

Summary: Direct glucose production links G6PC1 catalysis to glucose homeostasis.

Reason: Human loss-of-function variants in PMID:8211187 and the known glucose-6-phosphate hydrolysis reaction establish the enzyme's contribution to maintaining circulating glucose. G6PC1 performs the productive chemical step rather than merely reporting a downstream phenotype. This does not make it a glucose transporter or imply equivalent systemic roles for G6PC2 and G6PC3.

Summary: Chemical homeostasis is covered by the supported, more specific glucose-homeostasis term.

Reason: The unchanged ARBA assertion is biologically compatible with G6PC1 function, but official GO ancestry places glucose homeostasis under chemical homeostasis. The specific process is already accepted with direct human and biochemical support, so the broad category adds no distinct functional coverage.

Summary: Glucose-6-phosphate metabolism includes the directly demonstrated hydrolysis catalyzed by G6PC1.

Reason: The rat donor includes experimental PMID:4303362, whose authentic abstract assays glucose-6-phosphatase in developing kidney and relates it to glucose formation. More directly, human enzyme experiments establish turnover of glucose-6-phosphate itself. The process is therefore core biochemical participation; no exact developmental timing is generalized from rat to human.

Summary: Altered G6PC abundance perturbs lipid homeostasis through metabolic coupling.

Reason: The exact rat donor IMP cites PMID:9813078. The authentic original abstract reports hepatic G6Pase overexpression followed by changes in glycogen, circulating fatty acids/triglycerides and peripheral lipid stores. This supports a physiological metabolic consequence while leaving the core reaction as glucose-6-phosphate hydrolysis. It does not establish that G6PC1 directly catalyzes lipid synthesis, lipid transport or a lipid-specific reaction.

Summary: The exact rat experiment supports a non-core G6pc expression response to resveratrol.

Reason: Selected original Methods/Results of PMID:27366200 measure hepatic G6pc mRNA by qPCR in insulin-treated diabetic Wistar rats. Adjunct resveratrol lowers G6pc expression relative to insulin alone. GO response terms include gene-expression changes, so experimental drug exposure is not by itself over-annotation. Preserve rat orthology and treatment context; do not infer direct resveratrol binding, a SIRT1 catalytic role for G6PC1 or universal human drug-response behavior.