G6pc2

Summary: Glucose-6-phosphatase activity inherited from the PTHR12591 root node PTN000971890; the catalytic activity is shared by all three G6PC paralogs and is experimentally established for mouse G6pc2 itself.

Reason: The IBD for GO:0004346 sits at the eumetazoan G6PC node and is seeded by experimental annotations of G6PC1, G6PC3 and G6PC2 from human, mouse and rat. Mouse G6pc2 (MGI:1277193) appearing among the seeds is expected: its own IDA and IMP rows are descendant evidence for the node. G6pc2 retains the PAP2 catalytic machinery (UniProt active sites His115 and His174), recombinant IGRP hydrolyses G6P with a sub-millimolar Km (PMID:14722102), and islets from knockout mice lose glucose-6-phosphatase activity and glucose cycling (PMID:23274894, PMID:25552595). `just paint-losses` reports no IRD or IKR on the G6pc2 lineage. The activity is low compared with G6pc1, but it is the protein's own reaction, it is the islet enzyme for that reaction (G6pc1 is not detected in islets), and its loss has an in vivo phenotype, so it is a core evolved function rather than a promiscuous side activity.

Summary: Recombinant IGRP overexpressed in insect cells hydrolyses glucose 6-phosphate with Km 0.29-0.45 mM; a selective small-molecule inhibitor distinguishes it from the liver enzyme.

Reason: Direct enzymology of the target protein: the abstract reports Michaelis-Menten parameters for G6P hydrolysis and an inhibitor that blocks IGRP but not liver G6Pase, ruling out a contaminating phosphatase. It overturned the earlier failure to detect activity (PMID:10078553) and is corroborated by loss of islet activity in knockout mice (PMID:23274894) and by microsomal assays of transfected mouse G6PC2 (PMID:34954144). The abstract does not name the species of the construct; UniProt attributes the catalytic activity of the mouse entry to this paper (ECO:0000269), and mouse and human G6PC2 are 84% identical, so the claim is sound for mouse either way. Turnover is far below G6pc1 (PMID:34954144, PMID:38431189), but the low rate is what lets G6pc2 modulate rather than abolish glucokinase flux in beta cells, which is its physiological role.

Summary: Combined electronic assignment from the glucose-6-phosphatase family signature (IPR016275), the Rhea reaction and EC 3.1.3.9.

Reason: The electronic mapping agrees with the experimental evidence for this protein. G6pc2 is a member of the glucose-6-phosphatase family (InterPro IPR016275, PIRSF000905, PANTHER PTHR12591:SF1) and its curated UniProt catalytic-activity line, tied to PMID:14722102, gives the same reaction. Same claim as the accepted IDA and IMP rows.

Summary: Islets from G6pc2 knockout mice on a C57BL/6J background have reduced glucose-6-phosphatase activity.

Reason: Loss-of-function evidence on the endogenous mouse protein in its native cell. The radioisotopic G6P hydrolysis assay in permeabilised islets shows that G6pc2 accounts for the islet activity, consistent with the recombinant enzymology. Later work from the same group showed that knockout islets have no glucose cycling (PMID:25552595), which ties the activity to its physiological substrate flux.

Summary: Orthology transfer from human G6PC2 (Q9NQR9); human G6PC2 hydrolyses G6P with low turnover.

Reason: The claim is correct for mouse G6pc2 and is already established by direct mouse evidence (IDA, IMP), so this row adds little independent weight. The human donor's experimental row (a Reactome EXP) cites the same PMID:14722102, so the transfer is not an independent line. Human and mouse G6PC2 both show measurable microsomal G6Pase activity when expressed in islet-derived 832/13 cells (PMID:34954144).

Summary: ER location inherited from the G6PC family node; all three paralogs are ER-resident integral membrane enzymes.

Reason: Root organelle term, which is informative and stays. Checking what the IBA rests on: the IBD is seeded by mouse G6pc2 itself, mouse G6pc1 and G6pc3 and human G6PC3, and the organelle claim holds for G6pc2 on independent grounds: nine predicted transmembrane helices, a C-terminal ER-retention motif, translocation and glycosylation in microsomes (PMID:10078553), activity measured in microsomal membranes (PMID:34954144), and direct ER localisation of human IGRP (PMID:15044018). The row stops at the organelle because that is what the seed annotations assert; the ER membrane sub-compartment is already carried by the IEA and ISS rows below.

Summary: ER location is correct for G6pc2, but the cited paper is a localisation study of the Niemann-Pick C1 protein whose abstract does not mention G6pc2/IGRP.

Reason: The claim is clearly true: G6pc2 is an ER-resident multi-pass membrane protein (PMID:23274894, PMID:10078553, PMID:15044018). The cited reference is doubtful. The cached abstract states that the study determines the localisation of murine NPC1 by subcellular fractionation and microscopy, and names no other protein whose localisation was assayed. The full text could not be retrieved (the journal site returned HTTP 403), so it cannot be excluded that the paper used IGRP as an ER marker; the annotation is kept and the reference flagged to MGI as a suspected wrong reference rather than removed.

Summary: ARBA machine-learning assignment of ER location; correct for this protein.

Reason: The ARBA prediction itself is not evidence, but the organelle claim is independently supported by the protein's topology and retention signal and by ER localisation of the human ortholog (PMID:15044018). Same claim as the accepted IBA and IDA rows; the more specific ER membrane term is carried separately.

Summary: UniProt subcellular-location mapping to ER membrane; correct and the right granularity.

Reason: Several independent lines agree on the ER membrane: nine predicted transmembrane helices with a luminal active site, a C-terminal ER-retention motif, membrane translocation and glycosylation in a microsomal system (PMID:10078553), ER-embedded human IGRP held by nine transmembrane domains (PMID:15044018), and activity measured in isolated microsomal membranes (PMID:34954144). This is where the catalytic activity acts.

Summary: Cloning paper: IGRP shares the transmembrane topology of liver G6Pase, carries an ER retention signal and is translocated and glycosylated in microsomal membranes.

Reason: The sequence-similarity inference to the liver enzyme's ER-membrane location is sound and is backed by the in vitro translocation and glycosylation data in the same paper and by the later topology study of human IGRP (PMID:15044018). ER membrane is the location where the luminal-facing active site works.

Summary: Gluconeogenesis propagated from the root G6PC node to the islet paralog. G6pc2 is a beta-cell enzyme that cycles glucokinase-derived glucose 6-phosphate back to glucose to tune insulin secretion; it does not take part in glucose production from non-carbohydrate precursors.

Reason: The IBD for gluconeogenesis was placed at PTN000971890, the eumetazoan node ancestral to G6PC1, G6PC2 and G6PC3, and is seeded only by G6PC1 (human, mouse, rat), G6pc3 (mouse, rat) and a Drosophila member; no G6PC2 is a seed. `just paint-losses mouse G6pc2` finds no IRD or IKR on the lineage, so the row is current and the disagreement is with the node reaching the G6PC2 clade. Target-specific evidence shows the process role diverged in that clade while the catalytic machinery was retained. (1) G6pc2 is restricted to islet beta cells; the cloning paper found no other major tissue source, and the Vanderbilt group concluded that G6PC2 is highly unlikely to act in peripheral tissues, where G6pc1 and G6pc3 are far more abundant and more active. (2) In beta cells its substrate is G6P made from glucose by glucokinase, so its activity forms a futile substrate cycle that lowers glycolytic flux, not a route from pyruvate, lactate, glycerol or amino acids to glucose (the GO definition of gluconeogenesis). (3) The knockout phenotype is explained by insulin secretion: beta-cell-specific deletion alone is sufficient to lower fasting glucose, and the hypoglycaemia seen on prolonged fasting or a ketogenic diet is therefore a beta-cell effect on insulin output, not reduced glucose production, since islets do not supply blood glucose. Alpha-cell-specific deletion also lowers fasting glucose, by lowering glucagon rather than by changing insulin (PMID:39742505), which strengthens the point rather than weakening it: both arms of the fasting-glucose phenotype are islet-hormonal, and neither involves glucose output by the islet. Bgee expression, used here only as a paralog-controlled consistency check, agrees: in the gluconeogenic tissues (liver, kidney cortex, small intestine) G6pc2 has 10 absent calls and only low-scoring present calls (best 55), with one of its top-10 tissues in that context, whereas the sister paralog G6pc1 is present at scores near 98 and has six of its top-10 tissues there. G6pc2 does have low present calls in adult liver (scores 46-60), matching the trace extra-islet expression reported in PMID:12878201 and PMID:32213654, so expression alone could not carry this decision. A follow-up literature search found one direct measurement of glucose production bearing on G6PC2: among Danish elderly twins, carriers of the fasting-glucose raising rs560887 G allele had higher basal hepatic glucose production during a clamp (p = 0.04; PMID:19669124). That is a nominal association in a small subgroup, at a locus that also contains ABCB11, and is compatible with a higher defended glucose level; Pound et al. considered a hepatic G6PC2 role and judged it less likely because G6PC2 is expressed in islets and not liver (PMID:23274894). No study found measures glucose production or gluconeogenic flux in G6pc2-null mice, which would settle the residual question; it is recorded as a suggested experiment. A blinded OpenScientist function-assignment run, given the term and four cited papers but not this review's decision, its rationale or the Bgee report, independently judged the process refuted (file:mouse/G6pc2/G6pc2-hypotheses/function-hypothesis-go-0006094/openscientist.md). It argued from the literature alone and proposed an expression-atlas cross-check as its first confirmatory test, which the Bgee report supplies. Taken together the inherited process term is an over-propagation to a paralog that was co-opted for beta-cell glucose sensing; the electronic UniPathway row is removed for the same reason.

Summary: Electronic mapping from the UniProt PATHWAY line "Carbohydrate biosynthesis; gluconeogenesis", a family-level carry-over from G6pc1.

Reason: Same claim as the IBA row and removed for the same biological reasons. The UniProt PATHWAY line has no evidence tag and the FUNCTION text it accompanies is a hedged by-similarity statement ("May be responsible for glucose production through glycogenolysis and gluconeogenesis"). The experimental literature on mouse G6pc2 places its activity in a beta-cell glucose/G6P cycle that regulates insulin secretion; it is not expressed in the gluconeogenic tissues at meaningful levels and has no role in glucose production there (PMID:23274894, PMID:32213654).

Summary: Generic membrane location inherited from the G6PC node; true but less specific than the supported ER membrane location.

Reason: The membrane claim is correct (nine transmembrane helices), but the evidence supports the specific membrane: G6pc2 is an ER-resident multi-pass protein with an ER-retention motif, and the gene already carries GO:0005789 endoplasmic reticulum membrane by IEA and ISS. Refine to that descendant.

Proposed replacements: endoplasmic reticulum membrane

Summary: Ensembl Compara transfer from human G6PC2; G6pc2 sets the fasting blood glucose level in mice.

Reason: Directly supported by mouse genetics, independent of the human source. Global G6pc2 deletion lowers fasting blood glucose by 11-16% with unchanged fasting insulin (PMID:17265032, PMID:23274894), beta-cell-specific deletion is sufficient for this (PMID:32213654), and knockout mice become hypoglycaemic on prolonged fasting or a ketogenic diet (PMID:32569842). The activity is the mechanism: by cycling G6P back to glucose in the beta cell, G6pc2 shifts the glucose threshold for insulin secretion and hence the blood glucose level at which the system settles. GO:0042593 has only one child (intracellular glucose homeostasis), which does not apply, so this term is as precise as warranted.

Summary: Orthology transfer from human G6PC2, whose own row rests on a fasting-glucose SNP association study; independently supported in mouse by knockout data.

Reason: The human source annotation (IMP, PMID:20668700) is a population association of a G6PC2 SNP with fasting glucose, which is weak as perturbation evidence for the protein. The transferred claim is nevertheless well supported in mouse: G6pc2 deletion lowers fasting glucose in several genetic backgrounds (PMID:28122818) and beta-cell-specific deletion is sufficient (PMID:32213654). Same claim as the IEA row above.

Summary: Ensembl Compara transfer from human G6PC2; correct but less specific than the mouse data support: G6pc2 negatively regulates glucose-stimulated insulin secretion.

Reason: Mouse experiments establish the direction and the stimulus. G6pc2 deletion enhances insulin secretion from perfused pancreas and isolated islets about 2-fold at submaximal glucose (5-11 mM) but not at 16.7 mM, i.e. a leftward shift of the glucose dose-response (PMID:23274894); CRISPR deletion in a mouse beta-cell line raises glycolytic and citric acid cycle flux and doubles GSIS (PMID:35176280). G6pc2 does part of the work: its own G6P hydrolysis opposes glucokinase at the entry to glycolysis, which is the step that sets the glucose sensitivity of insulin release. Refine to GO:0061179 negative regulation of insulin secretion involved in cellular response to glucose stimulus (an is_a descendant of GO:0050796 via GO:0046676 and GO:0061178).

Proposed replacements: negative regulation of insulin secretion involved in cellular response to glucose stimulus

Summary: Orthology transfer from human G6PC2 (SNP association source); mouse knockout data support the more specific negative regulation of glucose-stimulated insulin secretion.

Reason: Same claim as the IEA row, refined for the same reason. The human source (IMP, PMID:20668700) associates a G6PC2 SNP with insulin secretion indices; the mouse evidence is direct and gives the sign: islets lacking G6pc2 secrete about 2.2-fold more insulin at 5 and 11 mM glucose, with no change at 16.7 mM (PMID:23274894), and the effect is mediated by loss of the glucose/G6P cycle (PMID:25552595).

Proposed replacements: negative regulation of insulin secretion involved in cellular response to glucose stimulus

Summary: Inducible alpha-cell-specific deletion of G6pc2 shifts the glucose set point for suppression of amino-acid-stimulated glucagon secretion leftward, so mutant islets release less glucagon at submaximal glucose and mutant mice have lower fasting and glucose-suppressed plasma glucagon with insulin unchanged.

Reason: This is the alpha-cell arm of G6pc2 function, demonstrated after the first version of this review was written and not covered by any existing row. Bahl et al. 2025 crossed a new G6pc2 conditional allele to Gcg-CreERT2 and ablated G6pc2 in 88% of alpha cells. Glucagon was stimulated with a 4 mM amino acid mixture and then suppressed with rising glucose; secretion at zero glucose was the same in both genotypes, but knockout islets secreted significantly less glucagon at 0.5, 1, 3 and 5 mM glucose, a leftward shift of the glucose response curve. In vivo both sexes had lower glucagon before and after a glucose load, with no difference in insulin, and the same during an insulin tolerance test and under phloridzin, which excludes a paracrine insulin explanation. Islet composition, alpha and beta cell proportions, proliferation and hormone content were unaffected, and 2-NBDG efflux assays confirmed the loss of futile cycling in the mutant alpha cells. Sign: losing G6pc2 lowers glucagon output at a given glucose, so G6pc2 is a positive regulator of glucagon secretion (GO:0070094, verified in OLS; is_a GO:0070092 and GO:0090277, no children). Participation: the regulated step is alpha-cell glycolytic flux and G6pc2's own G6P hydrolysis is what lowers it, opposing glucokinase, so the gene product does the work rather than merely being required. Comparator check: cell-intrinsic regulators of alpha-cell glucagon release carry these terms (Pask GO:0070092 IMP PMID:21181396, Kcnk16 GO:0070092 IMP PMID:29402588, Syt7 GO:0070092 IMP PMID:19171650, Ffar4 GO:0070094 IMP PMID:24742677; QuickGO annotation search by reference, re-run 2026-11-10), so there is no convention against annotating an intracellular islet enzyme here. This supersedes the expectation recorded in the earlier version of this review, which cited the roughly 20-fold beta-cell bias of mouse G6pc2 (PMID:39121091) and the unchanged fasting glucagon of germline knockouts as reasons not to annotate a mouse alpha-cell role: a cell-autonomous effect is demonstrable in mouse despite the low expression, and the same effect was reproduced in primary human alpha cells. The matching row is in the human G6PC2 review.