SLC37A4 (glucose-6-phosphate exchanger; G6PT/G6PT1) is a multi-pass endoplasmic reticulum membrane transporter of the SLC37 sugar-phosphate/phosphate exchanger family (major facilitator superfamily, organophosphate:Pi antiporter clade). It is the glucose-6-phosphate:inorganic-phosphate antiporter that translocates cytosolic glucose-6-phosphate (G6P) into the ER lumen in exchange for luminal inorganic phosphate. By importing G6P into the ER, it delivers the substrate to the luminal active site of the glucose-6-phosphatase catalytic subunits (G6PC1 in liver, kidney and intestine; G6PC3 ubiquitously, including neutrophils), and thereby carries out the terminal, glucose-releasing step shared by gluconeogenesis and glycogenolysis, playing a central role in interprandial blood-glucose homeostasis. Two alternatively spliced isoforms exist (isoform 2/vG6PT includes an extra exon-7 segment); both are active G6P transporters. Loss-of-function variants cause glycogen storage disease type Ib (von Gierke type Ib), combining the GSD Ia-like metabolic phenotype (fasting hypoglycemia, hepatomegaly, lactic acidemia, hyperlipidemia) with neutropenia, neutrophil dysfunction and inflammatory-bowel-disease-like features, reflecting the transporter's role in both the hepatic G6PC1 and the neutrophil G6PC3 systems. A distinct dominant variant (p.Arg423*) that removes the C-terminal ER-retention signal mislocalizes the transporter to the Golgi and causes a congenital disorder of glycosylation (CDG-IIw) with liver dysfunction and coagulopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing the active SLC37A4 protein in the ER membrane. This is the well-established site of action of the G6P/Pi antiporter and is directly supported by experimental localization data. Reason: The ER membrane is the correct, experimentally confirmed compartment for this transporter (see the IDA/EXP annotations below), and the phylogenetic inference is consistent with orthologs. Retain as a core localization. Supporting Evidence: PMID:21949678 The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane |
| GO:0061513 glucose 6-phosphate:phosphate antiporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation for the defining molecular function: glucose 6-phosphate:phosphate antiporter activity. This is the correct, most informative MF term and is heavily supported by experimental evidence. Reason: This is the core molecular function of SLC37A4/G6PT, confirmed biochemically in reconstituted proteoliposomes as a dual G6P/Pi antiporter. The IBA is at the right level of specificity. Supporting Evidence: PMID:18337460 our results suggest that G6PT has a dual role as a G6P and a P(i) PMID:21949678 The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi |
| GO:0015760 glucose-6-phosphate transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation for the biological process of glucose-6-phosphate transport, the direct process carried out by this antiporter. Reason: G6P transport across the ER membrane is the direct, core biological process of SLC37A4, supported by multiple experimental (IMP/IDA) annotations. Retain as core. Supporting Evidence: PMID:21949678 The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi |
| GO:0035435 phosphate ion transmembrane transport | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) annotation for phosphate ion transmembrane transport. Because SLC37A4 is an antiporter, inorganic phosphate is the counter-substrate moved in the opposite direction to G6P, so phosphate transport is a genuine part of its activity. Reason: Phosphate transport is real but is the counter-transport leg of the G6P:Pi antiport rather than the physiologically salient function; the G6P-directed terms capture the core role. Keep as a non-core aspect. Supporting Evidence: PMID:18337460 our results suggest that G6PT has a dual role as a G6P and a P(i) |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation (UniProt Subcellular Location mapping) placing SLC37A4 in the ER membrane. Correct and consistent with experimental localization. Reason: The UniProt SubCell mapping (SL-0097, ER membrane) is accurate and matches the experimentally determined localization. Retain. Supporting Evidence: PMID:32884905 The wildtype protein resides in the ER of HepG2 tetoff cells |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Electronic (InterPro2GO) annotation to the generic term "membrane". SLC37A4 is indeed a membrane protein, but this term is far less specific than the experimentally supported ER membrane localization. Reason: "membrane" is trivially true for a multi-pass transporter but uninformative given that the specific compartment (ER membrane) is well established. Over-annotation. Supporting Evidence: PMID:32884905 The wildtype protein resides in the ER of HepG2 tetoff cells |
| GO:0022857 transmembrane transporter activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Electronic (InterPro2GO) annotation to the very general MF "transmembrane transporter activity". Correct in essence but much broader than the specific G6P:Pi antiporter activity that is experimentally established. Reason: The specific antiporter activity (GO:0061513) and the G6P transmembrane transporter activity (GO:0015152) are the informative MF terms; the generic parent adds no information. Mark as over-annotated rather than removing an InterPro-based root term. Supporting Evidence: PMID:18337460 our results suggest that G6PT has a dual role as a G6P and a P(i) |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Electronic (InterPro2GO) annotation to the general BP "transmembrane transport". True but general relative to the specific glucose-6-phosphate transport process. Reason: Correct high-level process; the specific G6P transport (GO:0015760) is the core term. Keep as a valid but non-core parent. Supporting Evidence: PMID:21949678 The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI annotation to the uninformative "protein binding" term, from a high-throughput yeast-two-hybrid interactome map (HuRI) reporting an interaction with BIK (UniProtKB:Q13323). This is a bare binding annotation with no functional context. Reason: Per curation guidelines, bare "protein binding" is not informative about molecular function. The single high-throughput binary interaction (with BIK) has no established functional consequence for the G6P antiporter and should not be treated as a core function. Retained but flagged (not removed, per policy on IPI binding annotations). Supporting Evidence: PMID:32296183 HuRI is a systematic proteome-wide reference that links genomic |
| GO:0006094 gluconeogenesis | TAS Reactome:R-HSA-70263 | KEEP AS NON CORE | Summary: TAS (Reactome) annotation to gluconeogenesis. SLC37A4 supplies G6P to the ER-luminal glucose-6-phosphatase, carrying out the terminal, glucose-releasing step common to gluconeogenesis and glycogenolysis, so participation in gluconeogenesis is correct. Reason: SLC37A4 contributes to gluconeogenesis by delivering G6P for the final hydrolysis step, but its molecular activity is transport, not a gluconeogenic enzymatic step. Retain as a valid contributory (non-core) process annotation. Supporting Evidence: PMID:21949678 Together, the G6PT/G6Pase-Ξ± complex maintains interprandial glucose homeostasis |
| GO:0061513 glucose 6-phosphate:phosphate antiporter activity | EXP PMID:18337460 The glucose-6-phosphate transporter is a phosphate-linked an... | ACCEPT | Summary: Experimental annotation for the G6P:Pi antiporter activity, based on reconstituted proteoliposome transport assays demonstrating the dual G6P/Pi antiport function. Reason: Direct biochemical demonstration of the defining molecular function in proteoliposomes; a null mutant (p.R28H) abolished transport. Core function. Supporting Evidence: PMID:18337460 our results suggest that G6PT has a dual role as a G6P and a P(i) |
| GO:0061513 glucose 6-phosphate:phosphate antiporter activity | TAS Reactome:R-HSA-3229118 | ACCEPT | Summary: TAS (Reactome) annotation for the G6P:Pi antiporter activity across the ER membrane. Consistent with the experimental evidence. Reason: Correct, well-supported core molecular function; duplicate of the EXP/IDA/IBA antiporter annotations with an authoritative source. Supporting Evidence: PMID:18337460 our results suggest that G6PT has a dual role as a G6P and a P(i) |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:32884905 SLC37A4-CDG: Mislocalization of the glucose-6-phosphate tran... | ACCEPT | Summary: Experimental localization to the ER membrane; wild-type SLC37A4 resides in the ER (contrasted with the Golgi-mislocalizing R423* CDG variant). Reason: Direct experimental support for ER membrane localization of the wild-type protein. Core localization. Supporting Evidence: PMID:32884905 The wildtype protein resides in the ER of HepG2 tetoff cells |
| GO:0061513 glucose 6-phosphate:phosphate antiporter activity | EXP PMID:10026167 Inactivation of the glucose 6-phosphate transporter causes g... | ACCEPT | Summary: Experimental annotation for the antiporter activity based on functional characterization of the recombinant G6P transporter and the demonstration that GSD-1b mutations disrupt G6P transport. Reason: Foundational functional characterization establishing the molecular activity of the transporter and its loss in disease mutants. Core function. Supporting Evidence: PMID:10026167 mutations uncovered in GSD-1b patients disrupt G6P |
| GO:0061513 glucose 6-phosphate:phosphate antiporter activity | EXP PMID:33964207 A mutation in SLC37A4 causes a dominantly inherited congenit... | ACCEPT | Summary: Experimental annotation for the antiporter activity; SLC37A4 is required for transporting glucose-6-phosphate into the ER, where it is hydrolyzed to glucose and phosphate. Reason: Supports the transport/antiport function of the ER-localized transporter. Core molecular function. Supporting Evidence: PMID:33964207 required for transporting glucose-6-phosphate (Glc-6P) into the ER |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:33964207 A mutation in SLC37A4 causes a dominantly inherited congenit... | ACCEPT | Summary: IDA localization of SLC37A4 to the ER membrane (wild-type protein), consistent with other experimental localization data. Reason: Directly observed ER localization of the wild-type transporter. Core localization. Supporting Evidence: PMID:33964207 SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane |
| GO:0015760 glucose-6-phosphate transport | IMP PMID:10026167 Inactivation of the glucose 6-phosphate transporter causes g... | ACCEPT | Summary: IMP annotation for glucose-6-phosphate transport; GSD-1b mutations were shown to disrupt G6P transport, implicating SLC37A4 in this process. Reason: Mutational evidence directly links SLC37A4 to the G6P transport process. Core. Supporting Evidence: PMID:10026167 mutations uncovered in GSD-1b patients disrupt G6P |
| GO:0015760 glucose-6-phosphate transport | IMP PMID:33964207 A mutation in SLC37A4 causes a dominantly inherited congenit... | ACCEPT | Summary: IMP annotation for glucose-6-phosphate transport, from characterization of the SLC37A4 R423* variant and the transporter's role in importing G6P into the ER. Reason: Supports the core G6P transport process of SLC37A4. Core. Supporting Evidence: PMID:33964207 required for transporting glucose-6-phosphate (Glc-6P) into the ER |
| GO:0061513 glucose 6-phosphate:phosphate antiporter activity | IDA PMID:18337460 The glucose-6-phosphate transporter is a phosphate-linked an... | ACCEPT | Summary: IDA annotation for the G6P:Pi antiporter activity from proteoliposome transport assays (MGI-assigned; same primary paper as the EXP annotation). Reason: Direct assay of the dual G6P/Pi antiport function. Core molecular function. Supporting Evidence: PMID:18337460 our results suggest that G6PT has a dual role as a G6P and a P(i) |
| GO:0015760 glucose-6-phosphate transport | NAS PMID:9428641 Sequence of a putative glucose 6-phosphate translocase, muta... | ACCEPT | Summary: NAS annotation for glucose-6-phosphate transport based on the original cDNA cloning, identifying the protein as the glucose-6-phosphate translocase functionally associated with glucose-6-phosphatase. Reason: The founding paper assigns the G6P translocase role; concordant with later experimental evidence for the core transport process. Supporting Evidence: PMID:9428641 most likely the glucose 6-phosphate translocase that is |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:21949678 SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphat... | ACCEPT | Summary: IDA localization to the ER membrane, based on immunofluorescence co-localization with the ER marker calreticulin. Reason: Direct experimental support for ER membrane localization. Core localization. Supporting Evidence: PMID:21949678 The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane |
| GO:0015760 glucose-6-phosphate transport | IDA PMID:21949678 SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphat... | ACCEPT | Summary: IDA annotation for glucose-6-phosphate transport from reconstituted proteoliposome G6P uptake assays for G6PT/SLC37A4. Reason: Direct functional demonstration of G6P transport; core process. Supporting Evidence: PMID:21949678 The primary function of G6PT is to translocate G6P from the cytoplasm into the lumen of the ER for hydrolysis into glucose and Pi |
| GO:0035435 phosphate ion transmembrane transport | IDA PMID:21949678 SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphat... | KEEP AS NON CORE | Summary: IDA annotation for phosphate ion transmembrane transport, from proteoliposome assays showing Pi uptake as the counter-substrate of the G6P:Pi antiport. Reason: Pi transport is directly measured but represents the counter-transport leg of the antiporter; the G6P-directed function is the physiologically core role. Keep as non-core. Supporting Evidence: PMID:18337460 our results suggest that G6PT has a dual role as a G6P and a P(i) |
| GO:0061513 glucose 6-phosphate:phosphate antiporter activity | IDA PMID:21949678 SLC37A1 and SLC37A2 are phosphate-linked, glucose-6-phosphat... | ACCEPT | Summary: IDA annotation for the G6P:Pi antiporter activity from reconstituted proteoliposomes; G6PT is the physiological ER G6P antiporter that couples to glucose-6-phosphatase-Ξ±. Reason: Direct biochemical demonstration of the defining antiporter activity, including CHA sensitivity and coupling to G6Pase-Ξ± that distinguishes G6PT from other SLC37 members. Core function. Supporting Evidence: PMID:21949678 Taken together these findings suggest that only SCL37A4 contributes to interprandial blood glucose homeostasis |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput direct assay (membrane proteomics of an NK-like cell line) detecting SLC37A4 in the membrane fraction. Confirms membrane association but is unspecific. Reason: A proteomics hit to the generic "membrane" term adds nothing beyond the specific, experimentally established ER membrane localization. Over-annotation (kept, not removed). Supporting Evidence: PMID:19946888 approximately 40% of the identified proteins were predicted as plausible membrane proteins |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-3229118 | ACCEPT | Summary: TAS (Reactome) annotation for ER membrane localization, consistent with all experimental localization data. Reason: Correct core localization from an authoritative pathway source. Supporting Evidence: PMID:21949678 The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-198513 | ACCEPT | Summary: TAS (Reactome) annotation for ER membrane localization (G6P/Pi exchange reaction across the ER membrane). Reason: Correct core localization; concordant with experimental data. Supporting Evidence: PMID:21949678 The glucose-6-phosphate transporter (G6PT, also known as SLC37A4) is localized in the endoplasmic reticulum (ER) membrane |
| GO:0005783 endoplasmic reticulum | NAS PMID:212064 A new variant of glycogen storage disease type I probably du... | KEEP AS NON CORE | Summary: NAS annotation to the general "endoplasmic reticulum" term, from an early description of a GSD type I variant attributed to a defect in the G6P transport system. Reason: Correct compartment but less specific than the well-supported ER membrane term; the transporter is an integral membrane protein, so ER membrane is preferred. Keep as non-core / less specific. Supporting Evidence: PMID:212064 A new variant of glycogen storage disease type I probably due to a defect in the glucose-6-phosphate transport system |
| GO:0006006 glucose metabolic process | NAS PMID:9428641 Sequence of a putative glucose 6-phosphate translocase, muta... | KEEP AS NON CORE | Summary: NAS annotation to the broad "glucose metabolic process" term. SLC37A4 participates in glucose metabolism by supplying G6P for hydrolysis to glucose, but this is a very general process term. Reason: True but broad; the specific G6P transport and glucose homeostasis terms capture the informative process roles. Keep as non-core parent. Supporting Evidence: PMID:9428641 most likely the glucose 6-phosphate translocase that is |
| GO:0015152 glucose-6-phosphate transmembrane transporter activity | IMP PMID:12560945 The signature motif in human glucose-6-phosphate transporter... | ACCEPT | Summary: IMP annotation for glucose-6-phosphate transmembrane transporter activity; mutations in the transporter's signature motif abolish microsomal G6P uptake, showing the motif is required for G6P transport. Reason: Mutational evidence directly supports G6P transmembrane transporter activity. This is a correct, informative MF term (a close, slightly less specific companion to the G6P:Pi antiporter term). Core function. Supporting Evidence: PMID:12560945 the signature motif is a |
| GO:0015152 glucose-6-phosphate transmembrane transporter activity | IDA O43826-2 PMID:11140953 Human variant glucose-6-phosphate transporter is active in m... | ACCEPT | Summary: IDA annotation (on isoform 2, the variant vG6PT) for glucose-6-phosphate transmembrane transporter activity; vG6PT is active in microsomal G6P transport. The isoform field records what was assayed, not an isoform-unique function. Reason: Direct demonstration that isoform 2 also transports G6P confirms the MF and shows the exon-7 luminal-loop insertion does not impair transport. Core function (isoform 2). Supporting Evidence: PMID:11140953 vG6PT is also active in microsomal G6P |
| GO:0015760 glucose-6-phosphate transport | IMP PMID:12560945 The signature motif in human glucose-6-phosphate transporter... | ACCEPT | Summary: IMP annotation for glucose-6-phosphate transport; signature-motif mutants lack microsomal G6P uptake, implicating SLC37A4 in the transport process. Reason: Mutational evidence supports the core G6P transport process. Core. Supporting Evidence: PMID:12560945 required for microsomal glucose-6-phosphate transport |
| GO:0015760 glucose-6-phosphate transport | IDA O43826-2 PMID:11140953 Human variant glucose-6-phosphate transporter is active in m... | ACCEPT | Summary: IDA annotation (on isoform 2/vG6PT) for glucose-6-phosphate transport; the variant isoform is active in microsomal G6P transport. Reason: Direct evidence that isoform 2 carries out G6P transport. Core process (isoform 2); not a unique isoform function. Supporting Evidence: PMID:11140953 vG6PT is also active in microsomal G6P |
| GO:0016020 membrane | NAS PMID:9428641 Sequence of a putative glucose 6-phosphate translocase, muta... | MARK AS OVER ANNOTATED | Summary: NAS annotation to the generic "membrane" term based on the original cloning of a transmembrane protein with a C-terminal ER retention motif. Reason: The generic membrane term is subsumed by the specific ER membrane localization (the same paper notes the ER retention motif). Over-annotation. Supporting Evidence: PMID:9428641 presents at its carboxy terminus the consensus motif for retention in the |
| GO:0042593 glucose homeostasis | IDA O43826-2 PMID:11140953 Human variant glucose-6-phosphate transporter is active in m... | ACCEPT | Summary: IDA annotation (on isoform 2/vG6PT) for glucose homeostasis; the G6P transporter works together with glucose-6-phosphatase to maintain glucose homeostasis. Reason: SLC37A4/G6PT has a central, experimentally supported role in interprandial blood-glucose homeostasis by supplying G6P for hydrolysis to glucose. A core physiological process for this gene. Supporting Evidence: PMID:11140953 which works together with glucose-6-phosphatase to maintain glucose homeostasis |
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Download this section (compressed HTML)Q: Beyond the hepatic G6PC1 axis, how does G6PT (with the ubiquitous G6PC3) support neutrophil function, and what molecular mechanism links the transporter defect to neutropenia and neutrophil dysfunction in GSD Ib?
Q: Do the two SLC37A4 isoforms (canonical vs vG6PT) differ in tissue-specific regulation or kinetics despite both being active G6P transporters?
Experiment: Cryo-EM/functional dissection of the G6P:Pi antiport cycle to define the stoichiometry and the residues gating G6P entry versus Pi counter-transport (building on the 2025 structures), and test how GSD Ib missense variants perturb each half-cycle.
Experiment: Cell-based assays coupling G6PT with G6PC1 versus G6PC3 to quantify how the transporter partitions between the hepatic gluconeogenic and the neutrophil (energy/1,5-anhydroglucitol-6-phosphate detox) systems.
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