{"gene":"SLC2A5","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":1992,"finding":"GLUT5 (SLC2A5) functions as a high-affinity fructose transporter with a Km of 6 mM, exhibits selectivity for fructose over glucose, and is not inhibited by cytochalasin B (a competitive inhibitor of other facilitative glucose transporters). Established by expression of human GLUT5 mRNA in Xenopus oocytes with inhibition studies.","method":"Xenopus oocyte expression system, radiolabeled sugar uptake assays, inhibition studies with cytochalasin B","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro transport reconstitution in Xenopus oocytes with kinetic characterization, replicated across multiple subsequent studies","pmids":["1634504"],"is_preprint":false},{"year":1992,"finding":"GLUT5 protein is localized to the luminal (brush border) membrane of mature enterocytes in adult human small intestine, while in fetal small intestine it is found along intercellular junctions of developing villi, indicating developmental regulation of both expression and localization.","method":"Immunohistochemistry, Western blot of purified brush-border membranes","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct subcellular fractionation plus immunohistochemical localization, replicated across multiple labs","pmids":["1550217"],"is_preprint":false},{"year":1992,"finding":"GLUT5 is localized exclusively to the plasma membrane of human skeletal muscle cells, as demonstrated by subcellular fractionation showing enrichment in plasma-membrane fraction with minimal intracellular localization (~10%), confirmed by immunofluorescence.","method":"Subcellular fractionation, Western blot, immunofluorescence on cryostat sections","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation plus immunofluorescence, single lab, two orthogonal methods","pmids":["1530566"],"is_preprint":false},{"year":1992,"finding":"GLUT5 is expressed in human small intestine, kidney, heart, skeletal muscle, brain, and adipocyte plasma membranes. Insulin does not stimulate translocation of GLUT5 to the plasma membrane in adipocytes, indicating GLUT5 is a constitutive (non-insulin-responsive) sugar transporter.","method":"Immunoblotting, cytochalasin B photolabeling, immunoprecipitation, subcellular fractionation of adipocytes with/without insulin","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation experiment with insulin stimulation, cytochalasin B photolabeling confirming identity, single lab","pmids":["1397712"],"is_preprint":false},{"year":1993,"finding":"Rat GLUT5 expressed in Xenopus oocytes mediates uptake of fructose and, to a lesser extent, glucose. GLUT5 mRNA is developmentally regulated, with low prenatal levels and rapid postnatal induction in rat small intestine and kidney.","method":"Xenopus oocyte expression, radiolabeled sugar uptake, Northern blot, in situ hybridization","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro transport reconstitution replicated across species","pmids":["8333543"],"is_preprint":false},{"year":1994,"finding":"Cyclic AMP (cAMP) increases GLUT5 expression in Caco-2 cells by both stabilizing GLUT5 mRNA and increasing transcription, as demonstrated by forskolin treatment raising GLUT5 protein 5-fold and mRNA 7-fold, and by GLUT5 promoter-reporter gene assays showing cis-acting regulatory sequences mediate the effect.","method":"Forskolin treatment of differentiated Caco-2 cells, Northern/Western blot, GLUT5 promoter-reporter (luciferase) transfection assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter assay plus mRNA stability measurement, single lab, two orthogonal approaches","pmids":["8037665"],"is_preprint":false},{"year":1994,"finding":"Rabbit GLUT5 expressed in Xenopus oocytes mediates fructose transport with a Km of 11 mM. D-fructose transport by GLUT5 is inhibited by D-glucose and D-galactose in oocytes, and cytochalasin B photolabels GLUT5 in brush-border membrane preparations. GLUT5 is localized to the brush-border membrane of rabbit intestinal epithelial cells.","method":"Xenopus oocyte expression, radiolabeled fructose uptake, hybrid depletion with antisense oligonucleotide, immunoblot, cytochalasin B photolabeling, immunoprecipitation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including reconstitution, photolabeling, and hybrid depletion in single study","pmids":["7980458"],"is_preprint":false},{"year":1995,"finding":"GLUT5 is present not only in the brush-border membrane (BBM) but also in the basolateral membrane (BLM) of the human jejunum, with near-equal amounts per mg membrane protein in both fractions. Immunogold electron microscopy confirmed GLUT5 at both apical and basolateral membranes.","method":"Subcellular fractionation, quantitative immunoblotting, immunogold electron microscopy","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal fractionation with quantitative immunoblot plus ultrastructural immunogold localization, two orthogonal methods","pmids":["7619085"],"is_preprint":false},{"year":1995,"finding":"Rat GLUT5 expressed in CHO cells is targeted exclusively to the plasma membrane and transports fructose (Km = 11.6 mM) but not glucose, and is not photolabeled by cytochalasin B. Chimeric GLUT1/GLUT5 analysis showed that the intracellular middle loop and TM7-12 region are critical for GLUT1 glucose transport, while both the N-terminal half (including TM1-6) and the intracellular C-terminal region are required for GLUT5 fructose transport.","method":"Transfection into CHO cells, radiolabeled sugar uptake, cytochalasin B photolabeling, chimeric protein expression in Xenopus oocytes","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — chimeric protein domain-swap mutagenesis with functional transport assays, multiple constructs tested","pmids":["7588216"],"is_preprint":false},{"year":1995,"finding":"Fructose and glucose both increase GLUT5 expression in Caco-2 cells, with fructose being a stronger inducer (3-fold higher GLUT5 protein and mRNA vs. glucose). cAMP levels show a linear correlation with GLUT5 mRNA abundance in hexose-deprived cells, implicating cAMP signaling in sugar-induced GLUT5 regulation.","method":"Cell culture with defined sugar media, Northern/Western blot, cAMP measurement","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — correlation between cAMP and GLUT5 mRNA in multiple conditions, single lab","pmids":["8554516"],"is_preprint":false},{"year":1997,"finding":"Human GLUT5 expressed in Xenopus oocytes functions exclusively as a D-fructose transporter between pH 4.5 and 8.0 (Km ~15 mM at pH 7.5). Analysis with sugar analogues indicates GLUT5 preferentially transports D-fructose in the furanose ring form.","method":"Xenopus oocyte expression, radiolabeled sugar uptake, pH variation, sugar analogue inhibition studies","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro transport reconstitution with systematic analogue probing in Xenopus oocytes","pmids":["9299540"],"is_preprint":false},{"year":1997,"finding":"Human erythrocytes express GLUT5, which is the predominant transporter mediating fructose entry with an apparent Km ~10 mM. This transport is insensitive to 2-deoxy-D-glucose and cytochalasin B (which inhibit GLUT1/GLUT2), functionally distinguishing GLUT5-mediated fructose transport from other hexose transporters.","method":"Immunoblotting, immunolocalization, kinetic fructose transport studies, inhibitor studies in isolated erythrocytes","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (immunoblot plus functional transport assay), single lab","pmids":["9166863"],"is_preprint":false},{"year":1997,"finding":"Dietary fructose specifically enhances brush-border fructose transport rates and GLUT5 mRNA levels in weaning rats. Only luminal fructose (not glucose or sucrose without fructose) induces GLUT5 expression, and the effect is dose-dependent on luminal fructose concentration.","method":"In vivo dietary supplementation, intestinal brush-border vesicle transport assays, Northern blot","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo dietary manipulation with functional transport and mRNA measurement, single lab","pmids":["9124564"],"is_preprint":false},{"year":1998,"finding":"GLUT5 is expressed in the sarcolemma of rat skeletal muscle and mediates cytochalasin B-insensitive fructose uptake. Fructose-enriched diet for 4 days increased jejunal and renal GLUT5 but had no detectable effect on GLUT5 in skeletal muscle or adipocytes, indicating tissue-specific regulation.","method":"Subcellular fractionation, immunoblot, RT-PCR, sarcolemmal vesicle fructose uptake, cytochalasin B inhibition","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus functional transport assay plus dietary intervention, single lab","pmids":["9820812"],"is_preprint":false},{"year":1998,"finding":"GLUT5 in rat adipocytes mediates ~80% of total fructose uptake in a cytochalasin B-insensitive manner. GLUT5 is localized only to the adipocyte plasma membrane, and its cell-surface abundance is not modulated by insulin. In streptozotocin-diabetic rats, GLUT5 expression falls ~75% accompanied by ~50% reduction in fructose uptake.","method":"Subcellular fractionation, cytochalasin B inhibition assay, immunoblot, streptozotocin diabetes model","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus functional transport assay in multiple conditions, single lab","pmids":["9686924"],"is_preprint":false},{"year":1998,"finding":"Luminal (not endocrine) fructose signals regulate GLUT5 expression in weaning rat intestine, demonstrated by Thiry-Vella bypass surgery showing that intestinal loops lacking luminal contact with fructose had low GLUT5 mRNA and fructose transport despite systemic exposure.","method":"Thiry-Vella intestinal bypass surgery in weaning rats, radiolabeled sugar transport assays, Northern blot","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic surgical model with functional transport and mRNA readout, elegant epistatic design","pmids":["9486174"],"is_preprint":false},{"year":1999,"finding":"GLUT5 is localized to the apical plasma membrane of brush border microvilli in S3 proximal tubule cells of rat kidney outer medullary stripe, demonstrated by high-resolution immunofluorescence and immunogold electron microscopy.","method":"Immunofluorescence, immunogold electron microscopy, RT-PCR, immunoblot","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — ultrastructural immunogold localization plus immunofluorescence, two orthogonal methods","pmids":["10469370"],"is_preprint":false},{"year":1999,"finding":"Glucose and thyroid hormone (T3) co-regulate GLUT5 mRNA abundance in Caco-2/TC7 cells. Promoter deletion analysis localized glucose responsiveness to the -272/+41 fragment and T3 responsiveness to the -338/+41 region. EMSA demonstrated that thyroid hormone receptors α and β bind to the -308/-290 region of the GLUT5 promoter as THR/RXR heterodimers.","method":"GLUT5 promoter-luciferase reporter transfection, promoter deletion mapping, electrophoretic mobility shift assay (EMSA)","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter deletion mapping plus EMSA demonstrating direct receptor binding, single lab with multiple orthogonal methods","pmids":["10191252"],"is_preprint":false},{"year":2000,"finding":"ERK, p38, and PI3-kinase signaling pathways regulate intestinal fructose transport via GLUT5 and GLUT2. The ERK pathway restrains the p38 pathway; activation of p38 (by anisomycin) stimulates transport. GLUT2 undergoes rapid trafficking to the brush-border membrane within minutes (distinct from GLUT5), and GLUT2 intrinsic activity is regulated over a 9-fold range, while GLUT5 levels show minimal change during acute stimulation.","method":"Perfused isolated rat jejunal loops with pharmacological inhibitors (PD98059, SB203580, wortmannin), sugar transport assays, immunoblot","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with functional transport readout in perfused intestine, single lab","pmids":["10926840"],"is_preprint":false},{"year":2001,"finding":"Fructose-induced precocious induction of GLUT5 in weaning rat intestine requires de novo mRNA synthesis (blocked by actinomycin D) and de novo protein synthesis (blocked by cycloheximide), while glucose has no such effect. This demonstrates transcriptional and translational mechanisms underlying substrate-induced GLUT5 reprogramming.","method":"In vivo intestinal perfusion in weaning rats, actinomycin D and cycloheximide injection, radiolabeled fructose uptake, Northern blot","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological blockade of transcription/translation in vivo with functional transport readout, single lab","pmids":["11123204"],"is_preprint":false},{"year":2002,"finding":"Mouse GLUT5 expressed in Xenopus oocytes mediates fructose transport with a Kt of 13 mM. The GLUT5 gene uses alternative transcriptional initiation sites in somatic versus germ cells. The 5' flanking region contains CdxA, USF, and SRY binding sites potentially responsible for tissue-specific and dietary fructose-dependent expression.","method":"Xenopus oocyte expression, radiolabeled fructose uptake, 5'RACE, Northern blot, genomic sequence analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in oocytes plus 5'RACE characterization, single lab","pmids":["12031501"],"is_preprint":false},{"year":2003,"finding":"Fructose increases GLUT5 mRNA stability via cAMP signaling in Caco-2 cells: fructose raises cAMP more than glucose, which correlates with GLUT5 mRNA half-life. A 140 kDa RNA-protein complex binds the GLUT5 3'-UTR more strongly in sugar-deprived cells; PABP-interacting protein 2 (Paip2), a destabilizing partner of PABP, was identified as a component of GLUT5 3'-UTR RNA-protein complexes.","method":"GLUT5 promoter-reporter assay, PKA inhibitor treatment, mRNA half-life measurement, RNA-protein binding assays, protein identification","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA stability assay plus RNA-protein binding characterization with Paip2 identification, single lab, multiple methods","pmids":["12820898"],"is_preprint":false},{"year":2003,"finding":"Long-term (24 h) insulin treatment of L6 skeletal muscle cells induces a dose-dependent ~2-fold increase in GLUT5 protein and fructose uptake. This effect is suppressed by inhibitors of transcription and protein synthesis, and insulin increases GLUT5 promoter activity ~1.8-fold, indicating de novo transcriptional induction.","method":"L6 cell culture with insulin treatment, Western blot, fructose uptake assay, GLUT5 promoter-luciferase transfection, inhibitor studies","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assay plus functional transport assay plus inhibitor studies, single lab","pmids":["12914929"],"is_preprint":false},{"year":2007,"finding":"Dexamethasone (a glucocorticoid) sensitizes the neonatal rat intestine to fructose-induced GLUT5 induction. Dexamethasone alone before weaning (when pups are <14 days) allows luminal fructose to precociously stimulate GLUT5 expression and fructose absorption. This age-dependent sensitization is specific to GLUT5 and does not affect SGLT1 or GLUT2.","method":"In vivo rat intestinal perfusion model, dexamethasone IP injection in neonatal rats, microarray hybridization, radiolabeled fructose uptake","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological intervention with functional transport readout plus gene expression profiling, single lab","pmids":["17947353"],"is_preprint":false},{"year":2008,"finding":"Glucocorticoid receptor (GR) mediates dexamethasone sensitization of GLUT5 induction in neonatal rat intestine. GR antagonist RU486 dose-dependently blocked dexamethasone effects on GLUT5 and arginase2. GR nuclear translocation occurred only when dexamethasone-injected pups were perfused with fructose, accompanied by increased GLUT5 abundance. Actinomycin D prevented dexamethasone-induced synthesis of an intermediate required for fructose-induced GLUT5 regulation.","method":"Receptor antagonist/agonist pharmacology in vivo, GR nuclear translocation assay, actinomycin D treatment, immunoblot","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological receptor dissection plus GR localization, multiple inhibitors, single lab","pmids":["18556366"],"is_preprint":false},{"year":2008,"finding":"Fructose transporter Glut5 (Slc2a5) is essential for fructose-induced hypertension. Knockout of Slc2a5 in mice reduces jejunal fructose absorption and prevents fructose-induced increases in intestinal NaCl/water absorption and hypertension. Dietary fructose enhances expression of Slc2a5 and the chloride transporter Slc26a6 in mouse small intestine.","method":"Slc26a6 knockout mice, blood pressure measurement, dietary fructose feeding, immunoblot/expression analysis","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout model with physiological phenotypic readout, single lab","pmids":["18496516"],"is_preprint":false},{"year":2009,"finding":"Luminal leptin activates PKCβII and AMPKα signaling, leading to insertion of GLUT5 (and GLUT2) into the brush-border membrane and enhanced fructose transport. In vivo, oral fructose triggers rapid gastric leptin release, which in turn upregulates GLUT5-mediated fructose transport via this regulatory loop.","method":"In vitro and in vivo isolated rat/mouse jejunal loops, leptin receptor signaling inhibitors, AMPK knockout mice, sugar transport assays, immunoblot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — signaling pathway dissection with AMPK knockout mice and pharmacological inhibitors, multiple orthogonal approaches, single lab","pmids":["19956534"],"is_preprint":false},{"year":2011,"finding":"Fructose-induced expression of GLUT5 during intestinal development is epigenetically regulated: fructose perfusion and age both increase Pol II binding and histone H3 acetylation at the Glut5 promoter. Glucocorticoid receptor (GR) translocates to the nucleus and binds the Glut5 promoter in an age- and fructose-dependent manner, while GR binding to the Sglt1 promoter was not observed.","method":"Chromatin immunoprecipitation (ChIP) for Pol II, GR, and histone acetylation marks; intestinal perfusion in 10- and 20-day-old rats; RT-PCR","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP assays with multiple antibodies plus GR nuclear binding, functional mRNA correlation, single lab with multiple orthogonal methods","pmids":["21222652"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of rat GLUT5 (open outward-facing) and bovine GLUT5 (open inward-facing) reveal a major facilitator superfamily fold. Comparison of inward-facing structures of GLUT5 and human GLUT1 shows a single point mutation suffices to switch substrate-binding preference from fructose to glucose. Transport mechanism involves global rocker-switch re-orientation plus local asymmetric rearrangements of C-terminal TM7 and TM10 helices ('gated-pore' mechanism).","method":"X-ray crystallography (crystal structures in two conformations), point mutation functional analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structures in two conformational states plus mutagenesis validation, single rigorous study","pmids":["26416735"],"is_preprint":false},{"year":2015,"finding":"Fructose-induced increases in intestinal fructolytic and gluconeogenic enzyme expression specifically require GLUT5 (for fructose uptake) and KHK (for intracellular fructose metabolism), as demonstrated in GLUT5-KO, KHK-KO, and Rab11a-KO mice. Blocking GLUT5 trafficking to the apical membrane (via Rab11a-KO) also impairs fructose-induced enzyme upregulation, placing GLUT5 upstream of KHK in a feed-forward fructose-sensing pathway.","method":"GLUT5 knockout, KHK knockout, intestinal epithelial cell-specific Rab11a knockout mice; dietary fructose gavage; intestinal mRNA and protein expression","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent genetic knockout models with functional gene expression readout, multiple orthogonal approaches","pmids":["26084694"],"is_preprint":false},{"year":2015,"finding":"Rubusoside and astragalin-6-glucoside inhibit human GLUT5 fructose transport. A key residue distinguishing GLUT1 (Trp388) from GLUT5 (Ala396) determines ligand specificity: GLUT1-W388A became susceptible to astragalin-6-glucoside; GLUT5-A396W gained glucose transport activity and maintained inhibitor sensitivity, demonstrating this position controls substrate selectivity.","method":"Transport activity assays in Xenopus oocytes expressing individual GLUTs, site-directed mutagenesis, in silico docking","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus functional transport assay in reconstituted system, single lab with multiple constructs","pmids":["26306809"],"is_preprint":false},{"year":2016,"finding":"MSNBA (N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine) is a specific inhibitor of human GLUT5 fructose transport in proteoliposomes and in MCF7 cells (competitive inhibition, KI = 3.2 μM). MSNBA does not inhibit GLUT2, GLUT1, GLUT3, GLUT4, or bacterial GlcPSe. Mutagenesis studies implicate H387 of GLUT5 in inhibitor binding near the active site.","method":"Virtual screening, proteoliposome transport assay, MCF7 cell fructose uptake, site-directed mutagenesis, ligand docking","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in proteoliposomes plus cell-based assay plus mutagenesis, single lab, multiple orthogonal methods","pmids":["27074918"],"is_preprint":false},{"year":2017,"finding":"Fructose transport by GLUT5 shows stringent stereochemical requirement: inversion of a single stereocenter at C-3, C-4, or C-5 of fructose abolishes GLUT5-mediated transport (shifting uptake to GLUT1). 6-NBDF (all D-fructose configuration) is taken up via GLUT5; C-3, C-4, C-5 epimers are not. In silico docking with the GLUT5 crystal structure confirms stereochemical dependence.","method":"Fluorescent hexose uptake assays in breast cancer cell lines, Xenopus oocyte expression, in silico docking with GLUT5 crystal structure","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based and oocyte uptake assays with multiple stereochemical probes, single lab","pmids":["28205432"],"is_preprint":false},{"year":2017,"finding":"Specific amino acid residues in GLUT5 required for fructose transport were identified using GLUT5/GLUT7 chimeras: critical positions reside in the first extracellular loop, TM5, TM7, TM8, TM9, TM10, and inter-TM loops 9-10 and 10-11. The Q167E substitution (analogous to rat Q166E) does not convert human GLUT5 into a glucose transporter but alters intracellular loop dynamics connecting TM6-7.","method":"Chimeric GLUT5/GLUT7 protein expression in NIH-3T3 cells, fructose radiotracer flux, fragment replacement analysis, molecular dynamics simulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic chimeric domain-swap analysis (26 fragments) with functional transport assay plus MD simulation, single lab","pmids":["29259131"],"is_preprint":false},{"year":2019,"finding":"LXRα (NR1H3) is a transcriptional regulator of GLUT5 expression. A functional LXR response element (LXRE) was identified at -385 bp relative to the GLUT5 transcriptional start site by promoter truncation and site-directed mutagenesis. LXR agonist T0901317 increases Glut5 mRNA and protein in mouse duodenum and adipose tissue in vivo.","method":"Unbiased GLUT5 promoter screen, promoter truncation reporter assay, site-directed mutagenesis of LXRE, LXR agonist treatment in mice, qPCR, Western blot","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter truncation plus mutagenesis of the LXRE plus in vivo agonist confirmation, single lab, multiple orthogonal methods","pmids":["31243309"],"is_preprint":false},{"year":2020,"finding":"AKT1 and AKT3 activation in drug-resistant colon cancer cells causes aberrant downregulation of miR-125b-5p, leading to increased GLUT5 expression. Restoring miR-125b-5p blocked GLUT5-dependent fructose metabolism. GLUT5 silencing with siRNA attenuated mesenchymal marker expression and migratory activity in chemoresistant cells.","method":"AKT1/3 inhibition, miR-125b-5p mimic transfection, siRNA knockdown of GLUT5, migration/invasion assays, metabolite measurement","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic interventions with functional phenotype readouts, single lab","pmids":["32649737"],"is_preprint":false},{"year":2021,"finding":"GLUT5 is sufficient to enable fructose-mediated cell proliferation across multiple cell types. GLUT5 overexpression in non-fructolytic cells enables growth in fructose medium; this fructose utilization occurs through glycolysis via hexokinase (HK), not ketohexokinase (KHK). Thus fructose uptake by GLUT5 is the limiting step for fructose-dependent proliferation.","method":"CRISPR-Cas9 KHK knockout, lentiviral GLUT5 overexpression in multiple cell lines, live cell imaging, Seahorse metabolic flux, LC/MS metabolomics, Crystal Violet assays","journal":"Cancer & metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell line panel, genetic KO and OE, metabolomics, multiple orthogonal methods in single study","pmids":["33762003"],"is_preprint":false},{"year":2021,"finding":"S100P promotes SLC2A5/GLUT5 expression in colorectal cancer by binding to a specific region of the SLC2A5 promoter, reducing its methylation levels, and activating transcription. This mechanism promotes CRC cell invasion and metastasis both in vitro and in vivo.","method":"Methylation mass spectrometry sequencing, methylation-specific PCR, bisulfite sequencing PCR, ChIP-qPCR, luciferase reporter assay, intrasplenic inoculation mouse model","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR plus promoter reporter assay plus methylation analysis, single lab, multiple methods","pmids":["34188196"],"is_preprint":false},{"year":2021,"finding":"GLUT5 deficiency reduces GLUT5-knockout mouse colitis severity upon fructose feeding compared to overexpression, mediated by changes in colonic microbiota (reversed by antibiotics). GLUT5 controls colonic fructose levels that shape gut microbiota composition and thereby modulate colitis severity.","method":"Glut5 knockout and overexpressor transgenic mice, DSS colitis model, dietary fructose feeding, fecal microbiota analysis, broad-spectrum antibiotics treatment","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse models with mechanistic microbiota link shown by antibiotic rescue, single lab","pmids":["34133236"],"is_preprint":false},{"year":2022,"finding":"IL-6 activates fructose uptake and fructolysis in cancer cells via STAT3-mediated transcriptional activation of GLUT5. STAT3 associates with the GLUT5 promoter region in response to IL-6. Knockdown of GLUT5 abolishes IL-6-induced fructose uptake and compromises IL-6-elicited tumor cell proliferation.","method":"IL-6 treatment, STAT3 ChIP, GLUT5 promoter binding assay, GLUT5 knockdown, fructose uptake assay, cell proliferation assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown with fructose uptake and proliferation readout, single lab","pmids":["35813468"],"is_preprint":false},{"year":2022,"finding":"GLUT5-mediated fructose utilization promotes lung cancer cell migration by upregulating AKT phosphorylation via a glycolysis/lactate/AKT pathway. SLC2A5 deletion blocked migration and AKT activation; glycolysis inhibitor 2-DG and GLUT5-specific inhibitor 2,5-AM suppressed migration and AKT activation. In vivo tail-vein metastasis experiments confirmed reduced metastatic potential upon SLC2A5 deletion.","method":"CRISPR/Cas9 SLC2A5 deletion, retrovirus SLC2A5 overexpression, Transwell migration assay, Western blot for AKT phosphorylation, lactate assay, 2-DG and 2,5-AM inhibitor experiments, tail-vein metastasis mouse model","journal":"Clinical & translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus OE plus pharmacological inhibition with signaling readout in vitro and in vivo, single lab","pmids":["36454516"],"is_preprint":false},{"year":2022,"finding":"CRISPR/Cas9-mediated inactivation of SLC2A5 inhibits cancer cell migration and metastasis in vivo. SLC2A5-attenuated cells show dramatic alterations in mitochondrial architecture and localization, revealing a role for GLUT5 in directing mitochondrial function for cancer cell motility.","method":"CRISPR/Cas9 gene inactivation, in vitro migration assays, multiple in vivo animal metastasis models, mitochondrial imaging","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO in multiple cell lines and animal models with mitochondrial phenotype, single lab","pmids":["36268513"],"is_preprint":false},{"year":2023,"finding":"Molecular dynamics simulations show GLUT5 spontaneously transitions through an occluded state resembling PfHT1, with TM7b gating helix rearrangements. D-fructose coordination lowers the energetic barriers between outward- and inward-facing states. The binding mode is consistent with biochemical analysis, and GLUT5 uses allosteric coupling of sugar binding with extracellular gate closure (via TM7b) to achieve substrate selectivity, rather than achieving high affinity through substrate-binding site alone.","method":"Enhanced sampling molecular dynamics simulations, biochemical fructose transport analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — computational structural dynamics validated by biochemical transport data, single study","pmids":["37405832"],"is_preprint":false},{"year":2007,"finding":"GLUT5 physically interacts with prestin in cochlear outer hair cells. Using FRET (by FACS, acceptor photobleaching, and FLIM) and co-immunoprecipitation in HEK293T cells, both homomeric prestin-prestin and heteromeric prestin-GLUT5 interactions were demonstrated.","method":"Co-immunoprecipitation, confocal colocalization, FRET-FACS, FRET-acceptor photobleaching, FRET-FLIM in HEK293T cells","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus multiple FRET methods confirming interaction, single lab, transfected cell system","pmids":["17443803"],"is_preprint":false},{"year":1998,"finding":"GLUT5 domains responsible for fructose transport were further mapped using GLUT5/GLUT3 chimeras: the GLUT5 N-terminus through TM3 and the segment between TM5 and TM11 are both necessary for fructose uptake. Chimeras lacking either region failed to transport fructose despite surface expression confirmed by biotin exofacial labeling.","method":"Chimeric GLUT5/GLUT3 protein expression in Xenopus oocytes, radiolabeled sugar uptake, exofacial biotin labeling","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic chimeric domain-swap analysis with functional uptake assay plus surface expression control, single lab","pmids":["9492009"],"is_preprint":false},{"year":2018,"finding":"d-Allulose is a substrate of GLUT5. Plasma d-allulose absorption was enhanced in fructose-pre-fed rats (with higher GLUT5 expression), and co-gavage with fructose competitively dampened d-allulose absorption. Radiotracer assay showed d-allulose inhibited D-[14C]-fructose uptake (54.8% at 50 mM), but with lower affinity than fructose itself (16.4% inhibition at 50 mM).","method":"Dietary prefeeding to modulate GLUT5, plasma allulose measurement, competitive radiotracer D-[14C]-fructose uptake assay","journal":"Food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive transport assay plus dietary GLUT5 induction as natural genetic variable, single lab","pmids":["30502192"],"is_preprint":false},{"year":2023,"finding":"SNAI1 and SNAI2 transcription factors repress SLC2A5/GLUT5 expression. Trichostatin A (HDAC inhibitor) induces SNAI1/SNAI2 expression, which in turn suppresses SLC2A5 transcription and sensitizes colon cancer cells to cisplatin and oxaliplatin.","method":"SNAI1/SNAI2 overexpression, trichostatin A treatment, RT-PCR, Western blot, cell viability assays","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcription factor overexpression with mRNA/protein readout, pharmacological HDAC inhibitor, single lab","pmids":["37062501"],"is_preprint":false}],"current_model":"SLC2A5/GLUT5 is a 12-transmembrane major facilitator superfamily fructose transporter that uses a gated-pore rocker-switch mechanism (with critical roles for TM7 and TM10 helices) to mediate facilitated diffusion of D-fructose (Km ~6–15 mM depending on species) but not glucose; its substrate selectivity is determined by specific residues in TM5, TM7–TM10, and extracellular loops (with a single point mutation sufficient to switch fructose-to-glucose preference), and its expression is transcriptionally regulated by luminal fructose (via glucocorticoid receptor nuclear translocation, histone H3/H4 acetylation at the Glut5 promoter, and cAMP/mRNA stabilization), thyroid hormone receptors, LXRα, STAT3 (downstream of IL-6), and AKT/miR-125b-5p signaling, while being constitutively localized at the plasma membrane independently of insulin; GLUT5 is required for intestinal fructose absorption, renal proximal tubule fructose reuptake, and adipocyte/skeletal muscle fructose utilization, and its overexpression in cancer cells enables fructose-dependent proliferation and metastasis via glycolysis/AKT activation and mitochondrial remodeling."},"narrative":{"mechanistic_narrative":"SLC2A5/GLUT5 is a plasma-membrane fructose transporter of the major facilitator superfamily that mediates cytochalasin B-insensitive, high-affinity facilitated diffusion of D-fructose (Km ~6–15 mM) but not glucose, providing the rate-limiting entry step for fructose into intestinal, renal, muscle, adipocyte, and erythrocyte tissues [PMID:1634504, PMID:8333543, PMID:9299540, PMID:9166863]. Crystal structures captured in outward- and inward-facing states reveal a rocker-switch transport cycle gated by local rearrangements of the TM7 and TM10 helices, and a single point mutation is sufficient to switch GLUT5 substrate preference between fructose and glucose, defining how a small set of residues across the first extracellular loop, TM5, and TM7–TM10 dictates strict fructose selectivity and furanose-form, stereochemically defined recognition [PMID:26416735, PMID:26306809, PMID:29259131, PMID:28205432]. GLUT5 localizes constitutively to the apical brush-border membrane of enterocytes and renal proximal tubule cells and to the sarcolemma and adipocyte plasma membrane independently of insulin-stimulated translocation [PMID:1550217, PMID:10469370, PMID:9686924, PMID:1397712]. Its expression is induced specifically by luminal fructose through a transcriptional and post-transcriptional program involving glucocorticoid receptor nuclear translocation and binding to the Glut5 promoter, histone H3 acetylation and Pol II recruitment, thyroid hormone receptor and LXRα response elements, and cAMP-dependent mRNA stabilization [PMID:9486174, PMID:21222652, PMID:18556366, PMID:10191252, PMID:31243309, PMID:12820898]. Physiologically, GLUT5 is required for intestinal fructose absorption and feed-forward induction of fructolytic enzymes upstream of ketohexokinase, and its loss prevents fructose-induced hypertension and alters microbiota-dependent colitis [PMID:26084694, PMID:18496516, PMID:34133236]. In cancer, GLUT5-mediated fructose uptake is sufficient to support fructose-dependent proliferation through hexokinase-driven glycolysis and drives migration and metastasis via a glycolysis/lactate/AKT axis and mitochondrial remodeling, with its expression controlled by IL-6/STAT3, AKT/miR-125b-5p, S100P-mediated promoter demethylation, and SNAI1/SNAI2 repression [PMID:33762003, PMID:36454516, PMID:36268513, PMID:35813468, PMID:32649737, PMID:34188196].","teleology":[{"year":1992,"claim":"Established the fundamental identity of GLUT5 as a fructose-selective transporter, distinguishing it functionally from the glucose-transporting GLUTs.","evidence":"Heterologous expression of human GLUT5 in Xenopus oocytes with radiolabeled sugar uptake and cytochalasin B inhibition studies","pmids":["1634504"],"confidence":"High","gaps":["Did not resolve the structural basis of fructose selectivity","Did not address tissue-specific physiological roles"]},{"year":1992,"claim":"Defined where GLUT5 acts in tissue, showing apical brush-border localization in enterocytes and developmental regulation of its targeting.","evidence":"Immunohistochemistry and Western blot of purified brush-border membranes from adult and fetal human intestine","pmids":["1550217","1530566","1397712"],"confidence":"High","gaps":["Mechanism of apical targeting not defined","Whether basolateral pools exist not resolved at this stage"]},{"year":1992,"claim":"Showed GLUT5 is a constitutive, non-insulin-responsive transporter, contrasting it with insulin-regulated GLUT4.","evidence":"Subcellular fractionation of adipocytes with/without insulin plus cytochalasin B photolabeling","pmids":["1397712","9686924"],"confidence":"Medium","gaps":["Single-lab fractionation","Did not exclude longer-term transcriptional insulin effects later observed in muscle"]},{"year":1995,"claim":"Began mapping the protein determinants of fructose transport using chimeric transporters, localizing function to the N-terminal half and C-terminal region.","evidence":"GLUT1/GLUT5 and GLUT5/GLUT3 chimeric protein expression in CHO cells and oocytes with sugar uptake assays","pmids":["7588216","9492009"],"confidence":"High","gaps":["Resolution limited to large domains, not individual residues","No structural model available"]},{"year":1997,"claim":"Refined the substrate-recognition profile, showing GLUT5 transports D-fructose in the furanose form across a broad pH range.","evidence":"Xenopus oocyte expression with sugar analogue inhibition and pH variation","pmids":["9299540","7980458"],"confidence":"High","gaps":["Residues mediating furanose recognition not identified","No co-structure with substrate"]},{"year":1998,"claim":"Demonstrated that luminal fructose, not endocrine signals, drives intestinal GLUT5 induction, establishing substrate-sensing as the regulatory input.","evidence":"Thiry-Vella intestinal bypass surgery in weaning rats with transport and Northern blot readout","pmids":["9486174","9124564"],"confidence":"High","gaps":["Molecular sensor of luminal fructose not identified","Did not connect signal to specific promoter elements"]},{"year":2003,"claim":"Resolved a post-transcriptional arm of GLUT5 regulation, linking cAMP to GLUT5 mRNA stability via 3'-UTR RNA-protein complexes.","evidence":"mRNA half-life measurement, PKA inhibition, RNA-protein binding assays identifying Paip2 in Caco-2 cells","pmids":["12820898","8037665","8554516"],"confidence":"Medium","gaps":["Direct functional role of Paip2 in destabilization not validated by depletion","Single lab"]},{"year":2011,"claim":"Connected fructose sensing to the chromatin level, showing GR nuclear translocation, promoter binding, and histone acetylation drive developmental GLUT5 induction.","evidence":"ChIP for Pol II, GR, and histone acetylation marks in perfused rat intestine of defined ages","pmids":["21222652","17947353","18556366"],"confidence":"High","gaps":["How fructose signal reaches GR not defined","Histone acetyltransferase responsible not identified"]},{"year":2015,"claim":"Provided the atomic-resolution mechanism, capturing outward- and inward-facing states and showing a single residue switches fructose-versus-glucose preference.","evidence":"X-ray crystallography of rat and bovine GLUT5 in two conformations plus point-mutation functional analysis","pmids":["26416735","26306809","29259131"],"confidence":"High","gaps":["No substrate-bound human structure","Conformational transition dynamics inferred, not directly observed"]},{"year":2015,"claim":"Placed GLUT5 upstream in a feed-forward fructose-sensing pathway required for fructolytic and gluconeogenic enzyme induction.","evidence":"GLUT5-KO, KHK-KO, and Rab11a-KO mice with dietary fructose gavage and gene expression readout","pmids":["26084694","18496516"],"confidence":"High","gaps":["Identity of the intracellular fructose-sensing signal not pinned down","Tissue specificity of feed-forward loop beyond intestine unclear"]},{"year":2019,"claim":"Expanded the transcriptional control network by identifying functional thyroid hormone receptor and LXRα response elements in the GLUT5 promoter.","evidence":"Promoter truncation and mutagenesis reporter assays, EMSA, and in vivo agonist treatment in mice","pmids":["31243309","10191252"],"confidence":"High","gaps":["Integration of multiple promoter inputs not modeled","Physiological context where each factor dominates unclear"]},{"year":2021,"claim":"Demonstrated GLUT5-mediated fructose uptake is the limiting and sufficient step for fructose-dependent cancer cell proliferation, routed through hexokinase rather than ketohexokinase.","evidence":"Lentiviral GLUT5 overexpression and KHK CRISPR-KO across multiple cell lines with metabolic flux and metabolomics","pmids":["33762003","32649737","34188196","35813468"],"confidence":"High","gaps":["Cell-type determinants of HK-versus-KHK routing not fully defined","In vivo tumor dependence on dietary fructose not addressed here"]},{"year":2022,"claim":"Linked GLUT5 fructose metabolism to malignant migration and metastasis via a glycolysis/lactate/AKT axis and mitochondrial remodeling.","evidence":"CRISPR SLC2A5 deletion plus overexpression with migration assays, AKT phosphorylation, pharmacological inhibition, and tail-vein metastasis models","pmids":["36454516","36268513","32649737"],"confidence":"Medium","gaps":["Mechanism linking fructose metabolism to mitochondrial architecture not resolved","Single lab for each model system"]},{"year":2023,"claim":"Provided a dynamic mechanistic refinement, showing fructose binding lowers transition barriers and that allosteric TM7b gating, not the binding site alone, confers selectivity.","evidence":"Enhanced-sampling molecular dynamics simulations validated against biochemical transport data","pmids":["37405832"],"confidence":"Medium","gaps":["Computational prediction lacks direct structural snapshot of the occluded state","Human transporter dynamics inferred from model"]},{"year":null,"claim":"How the multiple promoter inputs (GR, THR, LXRα, STAT3, S100P, SNAI1/2), post-transcriptional control, and the luminal fructose-sensing signal are integrated to set GLUT5 levels in a given cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of combinatorial GLUT5 transcriptional regulation","The proximal fructose sensor upstream of these factors is unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,4,6,8,10,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,3,7,14,16]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,4,25,29]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[29,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[36,40,41]}],"complexes":[],"partners":["SLC26A6","PRESTIN","PAIP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22732","full_name":"Solute carrier family 2, facilitated glucose transporter member 5","aliases":["Fructose transporter","Glucose transporter type 5, small intestine","GLUT-5"],"length_aa":501,"mass_kda":55.0,"function":"Functions as a fructose transporter that has only low activity with other monosaccharides (PubMed:16186102, PubMed:17710649, PubMed:28083649, PubMed:29548810, PubMed:8333543). Can mediate the uptake of 2-deoxyglucose, but with low efficiency (PubMed:1695905). Essential for fructose uptake in the small intestine (By similarity). Plays a role in the regulation of salt uptake and blood pressure in response to dietary fructose (By similarity). Required for the development of high blood pressure in response to high dietary fructose intake (By similarity)","subcellular_location":"Apical cell membrane; Cell membrane; Cell membrane, sarcolemma","url":"https://www.uniprot.org/uniprotkb/P22732/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC2A5","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC2A5","total_profiled":1310},"omim":[{"mim_id":"610371","title":"SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE TRANSPORTER), MEMBER 7; SLC2A7","url":"https://www.omim.org/entry/610371"},{"mim_id":"610367","title":"SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE TRANSPORTER), MEMBER 11; SLC2A11","url":"https://www.omim.org/entry/610367"},{"mim_id":"606142","title":"SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE TRANSPORTER), MEMBER 9; SLC2A9","url":"https://www.omim.org/entry/606142"},{"mim_id":"138230","title":"SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE/FRUCTOSE TRANSPORTER), MEMBER 5; SLC2A5","url":"https://www.omim.org/entry/138230"},{"mim_id":"114780","title":"CARBONIC ANHYDRASE VI; CA6","url":"https://www.omim.org/entry/114780"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":91.5},{"tissue":"intestine","ntpm":102.6},{"tissue":"skeletal muscle","ntpm":73.9},{"tissue":"testis","ntpm":71.3}],"url":"https://www.proteinatlas.org/search/SLC2A5"},"hgnc":{"alias_symbol":[],"prev_symbol":["GLUT5"]},"alphafold":{"accession":"P22732","domains":[{"cath_id":"1.20.1250.20","chopping":"8-214","consensus_level":"medium","plddt":93.4856,"start":8,"end":214},{"cath_id":"-","chopping":"219-259","consensus_level":"medium","plddt":91.1502,"start":219,"end":259},{"cath_id":"1.20.1250.20","chopping":"263-501","consensus_level":"medium","plddt":89.1637,"start":263,"end":501}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22732","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22732-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22732-F1-predicted_aligned_error_v6.png","plddt_mean":90.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC2A5","jax_strain_url":"https://www.jax.org/strain/search?query=SLC2A5"},"sequence":{"accession":"P22732","fasta_url":"https://rest.uniprot.org/uniprotkb/P22732.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22732/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22732"}},"corpus_meta":[{"pmid":"1634504","id":"PMC_1634504","title":"Fructose transporter in human spermatozoa and small intestine is GLUT5.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1634504","citation_count":413,"is_preprint":false},{"pmid":"18398011","id":"PMC_18398011","title":"Regulation of the fructose transporter GLUT5 in health and disease.","date":"2008","source":"American journal of physiology. 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Established by expression of human GLUT5 mRNA in Xenopus oocytes with inhibition studies.\",\n      \"method\": \"Xenopus oocyte expression system, radiolabeled sugar uptake assays, inhibition studies with cytochalasin B\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro transport reconstitution in Xenopus oocytes with kinetic characterization, replicated across multiple subsequent studies\",\n      \"pmids\": [\"1634504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"GLUT5 protein is localized to the luminal (brush border) membrane of mature enterocytes in adult human small intestine, while in fetal small intestine it is found along intercellular junctions of developing villi, indicating developmental regulation of both expression and localization.\",\n      \"method\": \"Immunohistochemistry, Western blot of purified brush-border membranes\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct subcellular fractionation plus immunohistochemical localization, replicated across multiple labs\",\n      \"pmids\": [\"1550217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"GLUT5 is localized exclusively to the plasma membrane of human skeletal muscle cells, as demonstrated by subcellular fractionation showing enrichment in plasma-membrane fraction with minimal intracellular localization (~10%), confirmed by immunofluorescence.\",\n      \"method\": \"Subcellular fractionation, Western blot, immunofluorescence on cryostat sections\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation plus immunofluorescence, single lab, two orthogonal methods\",\n      \"pmids\": [\"1530566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"GLUT5 is expressed in human small intestine, kidney, heart, skeletal muscle, brain, and adipocyte plasma membranes. Insulin does not stimulate translocation of GLUT5 to the plasma membrane in adipocytes, indicating GLUT5 is a constitutive (non-insulin-responsive) sugar transporter.\",\n      \"method\": \"Immunoblotting, cytochalasin B photolabeling, immunoprecipitation, subcellular fractionation of adipocytes with/without insulin\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation experiment with insulin stimulation, cytochalasin B photolabeling confirming identity, single lab\",\n      \"pmids\": [\"1397712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Rat GLUT5 expressed in Xenopus oocytes mediates uptake of fructose and, to a lesser extent, glucose. GLUT5 mRNA is developmentally regulated, with low prenatal levels and rapid postnatal induction in rat small intestine and kidney.\",\n      \"method\": \"Xenopus oocyte expression, radiolabeled sugar uptake, Northern blot, in situ hybridization\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro transport reconstitution replicated across species\",\n      \"pmids\": [\"8333543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Cyclic AMP (cAMP) increases GLUT5 expression in Caco-2 cells by both stabilizing GLUT5 mRNA and increasing transcription, as demonstrated by forskolin treatment raising GLUT5 protein 5-fold and mRNA 7-fold, and by GLUT5 promoter-reporter gene assays showing cis-acting regulatory sequences mediate the effect.\",\n      \"method\": \"Forskolin treatment of differentiated Caco-2 cells, Northern/Western blot, GLUT5 promoter-reporter (luciferase) transfection assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter assay plus mRNA stability measurement, single lab, two orthogonal approaches\",\n      \"pmids\": [\"8037665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Rabbit GLUT5 expressed in Xenopus oocytes mediates fructose transport with a Km of 11 mM. D-fructose transport by GLUT5 is inhibited by D-glucose and D-galactose in oocytes, and cytochalasin B photolabels GLUT5 in brush-border membrane preparations. GLUT5 is localized to the brush-border membrane of rabbit intestinal epithelial cells.\",\n      \"method\": \"Xenopus oocyte expression, radiolabeled fructose uptake, hybrid depletion with antisense oligonucleotide, immunoblot, cytochalasin B photolabeling, immunoprecipitation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including reconstitution, photolabeling, and hybrid depletion in single study\",\n      \"pmids\": [\"7980458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"GLUT5 is present not only in the brush-border membrane (BBM) but also in the basolateral membrane (BLM) of the human jejunum, with near-equal amounts per mg membrane protein in both fractions. Immunogold electron microscopy confirmed GLUT5 at both apical and basolateral membranes.\",\n      \"method\": \"Subcellular fractionation, quantitative immunoblotting, immunogold electron microscopy\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal fractionation with quantitative immunoblot plus ultrastructural immunogold localization, two orthogonal methods\",\n      \"pmids\": [\"7619085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Rat GLUT5 expressed in CHO cells is targeted exclusively to the plasma membrane and transports fructose (Km = 11.6 mM) but not glucose, and is not photolabeled by cytochalasin B. Chimeric GLUT1/GLUT5 analysis showed that the intracellular middle loop and TM7-12 region are critical for GLUT1 glucose transport, while both the N-terminal half (including TM1-6) and the intracellular C-terminal region are required for GLUT5 fructose transport.\",\n      \"method\": \"Transfection into CHO cells, radiolabeled sugar uptake, cytochalasin B photolabeling, chimeric protein expression in Xenopus oocytes\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chimeric protein domain-swap mutagenesis with functional transport assays, multiple constructs tested\",\n      \"pmids\": [\"7588216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fructose and glucose both increase GLUT5 expression in Caco-2 cells, with fructose being a stronger inducer (3-fold higher GLUT5 protein and mRNA vs. glucose). cAMP levels show a linear correlation with GLUT5 mRNA abundance in hexose-deprived cells, implicating cAMP signaling in sugar-induced GLUT5 regulation.\",\n      \"method\": \"Cell culture with defined sugar media, Northern/Western blot, cAMP measurement\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — correlation between cAMP and GLUT5 mRNA in multiple conditions, single lab\",\n      \"pmids\": [\"8554516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human GLUT5 expressed in Xenopus oocytes functions exclusively as a D-fructose transporter between pH 4.5 and 8.0 (Km ~15 mM at pH 7.5). Analysis with sugar analogues indicates GLUT5 preferentially transports D-fructose in the furanose ring form.\",\n      \"method\": \"Xenopus oocyte expression, radiolabeled sugar uptake, pH variation, sugar analogue inhibition studies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro transport reconstitution with systematic analogue probing in Xenopus oocytes\",\n      \"pmids\": [\"9299540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human erythrocytes express GLUT5, which is the predominant transporter mediating fructose entry with an apparent Km ~10 mM. This transport is insensitive to 2-deoxy-D-glucose and cytochalasin B (which inhibit GLUT1/GLUT2), functionally distinguishing GLUT5-mediated fructose transport from other hexose transporters.\",\n      \"method\": \"Immunoblotting, immunolocalization, kinetic fructose transport studies, inhibitor studies in isolated erythrocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (immunoblot plus functional transport assay), single lab\",\n      \"pmids\": [\"9166863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Dietary fructose specifically enhances brush-border fructose transport rates and GLUT5 mRNA levels in weaning rats. Only luminal fructose (not glucose or sucrose without fructose) induces GLUT5 expression, and the effect is dose-dependent on luminal fructose concentration.\",\n      \"method\": \"In vivo dietary supplementation, intestinal brush-border vesicle transport assays, Northern blot\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo dietary manipulation with functional transport and mRNA measurement, single lab\",\n      \"pmids\": [\"9124564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GLUT5 is expressed in the sarcolemma of rat skeletal muscle and mediates cytochalasin B-insensitive fructose uptake. Fructose-enriched diet for 4 days increased jejunal and renal GLUT5 but had no detectable effect on GLUT5 in skeletal muscle or adipocytes, indicating tissue-specific regulation.\",\n      \"method\": \"Subcellular fractionation, immunoblot, RT-PCR, sarcolemmal vesicle fructose uptake, cytochalasin B inhibition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus functional transport assay plus dietary intervention, single lab\",\n      \"pmids\": [\"9820812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GLUT5 in rat adipocytes mediates ~80% of total fructose uptake in a cytochalasin B-insensitive manner. GLUT5 is localized only to the adipocyte plasma membrane, and its cell-surface abundance is not modulated by insulin. In streptozotocin-diabetic rats, GLUT5 expression falls ~75% accompanied by ~50% reduction in fructose uptake.\",\n      \"method\": \"Subcellular fractionation, cytochalasin B inhibition assay, immunoblot, streptozotocin diabetes model\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus functional transport assay in multiple conditions, single lab\",\n      \"pmids\": [\"9686924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Luminal (not endocrine) fructose signals regulate GLUT5 expression in weaning rat intestine, demonstrated by Thiry-Vella bypass surgery showing that intestinal loops lacking luminal contact with fructose had low GLUT5 mRNA and fructose transport despite systemic exposure.\",\n      \"method\": \"Thiry-Vella intestinal bypass surgery in weaning rats, radiolabeled sugar transport assays, Northern blot\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic surgical model with functional transport and mRNA readout, elegant epistatic design\",\n      \"pmids\": [\"9486174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GLUT5 is localized to the apical plasma membrane of brush border microvilli in S3 proximal tubule cells of rat kidney outer medullary stripe, demonstrated by high-resolution immunofluorescence and immunogold electron microscopy.\",\n      \"method\": \"Immunofluorescence, immunogold electron microscopy, RT-PCR, immunoblot\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ultrastructural immunogold localization plus immunofluorescence, two orthogonal methods\",\n      \"pmids\": [\"10469370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Glucose and thyroid hormone (T3) co-regulate GLUT5 mRNA abundance in Caco-2/TC7 cells. Promoter deletion analysis localized glucose responsiveness to the -272/+41 fragment and T3 responsiveness to the -338/+41 region. EMSA demonstrated that thyroid hormone receptors α and β bind to the -308/-290 region of the GLUT5 promoter as THR/RXR heterodimers.\",\n      \"method\": \"GLUT5 promoter-luciferase reporter transfection, promoter deletion mapping, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter deletion mapping plus EMSA demonstrating direct receptor binding, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10191252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ERK, p38, and PI3-kinase signaling pathways regulate intestinal fructose transport via GLUT5 and GLUT2. The ERK pathway restrains the p38 pathway; activation of p38 (by anisomycin) stimulates transport. GLUT2 undergoes rapid trafficking to the brush-border membrane within minutes (distinct from GLUT5), and GLUT2 intrinsic activity is regulated over a 9-fold range, while GLUT5 levels show minimal change during acute stimulation.\",\n      \"method\": \"Perfused isolated rat jejunal loops with pharmacological inhibitors (PD98059, SB203580, wortmannin), sugar transport assays, immunoblot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with functional transport readout in perfused intestine, single lab\",\n      \"pmids\": [\"10926840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Fructose-induced precocious induction of GLUT5 in weaning rat intestine requires de novo mRNA synthesis (blocked by actinomycin D) and de novo protein synthesis (blocked by cycloheximide), while glucose has no such effect. This demonstrates transcriptional and translational mechanisms underlying substrate-induced GLUT5 reprogramming.\",\n      \"method\": \"In vivo intestinal perfusion in weaning rats, actinomycin D and cycloheximide injection, radiolabeled fructose uptake, Northern blot\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological blockade of transcription/translation in vivo with functional transport readout, single lab\",\n      \"pmids\": [\"11123204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse GLUT5 expressed in Xenopus oocytes mediates fructose transport with a Kt of 13 mM. The GLUT5 gene uses alternative transcriptional initiation sites in somatic versus germ cells. The 5' flanking region contains CdxA, USF, and SRY binding sites potentially responsible for tissue-specific and dietary fructose-dependent expression.\",\n      \"method\": \"Xenopus oocyte expression, radiolabeled fructose uptake, 5'RACE, Northern blot, genomic sequence analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in oocytes plus 5'RACE characterization, single lab\",\n      \"pmids\": [\"12031501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Fructose increases GLUT5 mRNA stability via cAMP signaling in Caco-2 cells: fructose raises cAMP more than glucose, which correlates with GLUT5 mRNA half-life. A 140 kDa RNA-protein complex binds the GLUT5 3'-UTR more strongly in sugar-deprived cells; PABP-interacting protein 2 (Paip2), a destabilizing partner of PABP, was identified as a component of GLUT5 3'-UTR RNA-protein complexes.\",\n      \"method\": \"GLUT5 promoter-reporter assay, PKA inhibitor treatment, mRNA half-life measurement, RNA-protein binding assays, protein identification\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA stability assay plus RNA-protein binding characterization with Paip2 identification, single lab, multiple methods\",\n      \"pmids\": [\"12820898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Long-term (24 h) insulin treatment of L6 skeletal muscle cells induces a dose-dependent ~2-fold increase in GLUT5 protein and fructose uptake. This effect is suppressed by inhibitors of transcription and protein synthesis, and insulin increases GLUT5 promoter activity ~1.8-fold, indicating de novo transcriptional induction.\",\n      \"method\": \"L6 cell culture with insulin treatment, Western blot, fructose uptake assay, GLUT5 promoter-luciferase transfection, inhibitor studies\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assay plus functional transport assay plus inhibitor studies, single lab\",\n      \"pmids\": [\"12914929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dexamethasone (a glucocorticoid) sensitizes the neonatal rat intestine to fructose-induced GLUT5 induction. Dexamethasone alone before weaning (when pups are <14 days) allows luminal fructose to precociously stimulate GLUT5 expression and fructose absorption. This age-dependent sensitization is specific to GLUT5 and does not affect SGLT1 or GLUT2.\",\n      \"method\": \"In vivo rat intestinal perfusion model, dexamethasone IP injection in neonatal rats, microarray hybridization, radiolabeled fructose uptake\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological intervention with functional transport readout plus gene expression profiling, single lab\",\n      \"pmids\": [\"17947353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Glucocorticoid receptor (GR) mediates dexamethasone sensitization of GLUT5 induction in neonatal rat intestine. GR antagonist RU486 dose-dependently blocked dexamethasone effects on GLUT5 and arginase2. GR nuclear translocation occurred only when dexamethasone-injected pups were perfused with fructose, accompanied by increased GLUT5 abundance. Actinomycin D prevented dexamethasone-induced synthesis of an intermediate required for fructose-induced GLUT5 regulation.\",\n      \"method\": \"Receptor antagonist/agonist pharmacology in vivo, GR nuclear translocation assay, actinomycin D treatment, immunoblot\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological receptor dissection plus GR localization, multiple inhibitors, single lab\",\n      \"pmids\": [\"18556366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fructose transporter Glut5 (Slc2a5) is essential for fructose-induced hypertension. Knockout of Slc2a5 in mice reduces jejunal fructose absorption and prevents fructose-induced increases in intestinal NaCl/water absorption and hypertension. Dietary fructose enhances expression of Slc2a5 and the chloride transporter Slc26a6 in mouse small intestine.\",\n      \"method\": \"Slc26a6 knockout mice, blood pressure measurement, dietary fructose feeding, immunoblot/expression analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout model with physiological phenotypic readout, single lab\",\n      \"pmids\": [\"18496516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Luminal leptin activates PKCβII and AMPKα signaling, leading to insertion of GLUT5 (and GLUT2) into the brush-border membrane and enhanced fructose transport. In vivo, oral fructose triggers rapid gastric leptin release, which in turn upregulates GLUT5-mediated fructose transport via this regulatory loop.\",\n      \"method\": \"In vitro and in vivo isolated rat/mouse jejunal loops, leptin receptor signaling inhibitors, AMPK knockout mice, sugar transport assays, immunoblot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — signaling pathway dissection with AMPK knockout mice and pharmacological inhibitors, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"19956534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fructose-induced expression of GLUT5 during intestinal development is epigenetically regulated: fructose perfusion and age both increase Pol II binding and histone H3 acetylation at the Glut5 promoter. Glucocorticoid receptor (GR) translocates to the nucleus and binds the Glut5 promoter in an age- and fructose-dependent manner, while GR binding to the Sglt1 promoter was not observed.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for Pol II, GR, and histone acetylation marks; intestinal perfusion in 10- and 20-day-old rats; RT-PCR\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP assays with multiple antibodies plus GR nuclear binding, functional mRNA correlation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21222652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of rat GLUT5 (open outward-facing) and bovine GLUT5 (open inward-facing) reveal a major facilitator superfamily fold. Comparison of inward-facing structures of GLUT5 and human GLUT1 shows a single point mutation suffices to switch substrate-binding preference from fructose to glucose. Transport mechanism involves global rocker-switch re-orientation plus local asymmetric rearrangements of C-terminal TM7 and TM10 helices ('gated-pore' mechanism).\",\n      \"method\": \"X-ray crystallography (crystal structures in two conformations), point mutation functional analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structures in two conformational states plus mutagenesis validation, single rigorous study\",\n      \"pmids\": [\"26416735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fructose-induced increases in intestinal fructolytic and gluconeogenic enzyme expression specifically require GLUT5 (for fructose uptake) and KHK (for intracellular fructose metabolism), as demonstrated in GLUT5-KO, KHK-KO, and Rab11a-KO mice. Blocking GLUT5 trafficking to the apical membrane (via Rab11a-KO) also impairs fructose-induced enzyme upregulation, placing GLUT5 upstream of KHK in a feed-forward fructose-sensing pathway.\",\n      \"method\": \"GLUT5 knockout, KHK knockout, intestinal epithelial cell-specific Rab11a knockout mice; dietary fructose gavage; intestinal mRNA and protein expression\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent genetic knockout models with functional gene expression readout, multiple orthogonal approaches\",\n      \"pmids\": [\"26084694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rubusoside and astragalin-6-glucoside inhibit human GLUT5 fructose transport. A key residue distinguishing GLUT1 (Trp388) from GLUT5 (Ala396) determines ligand specificity: GLUT1-W388A became susceptible to astragalin-6-glucoside; GLUT5-A396W gained glucose transport activity and maintained inhibitor sensitivity, demonstrating this position controls substrate selectivity.\",\n      \"method\": \"Transport activity assays in Xenopus oocytes expressing individual GLUTs, site-directed mutagenesis, in silico docking\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus functional transport assay in reconstituted system, single lab with multiple constructs\",\n      \"pmids\": [\"26306809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MSNBA (N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine) is a specific inhibitor of human GLUT5 fructose transport in proteoliposomes and in MCF7 cells (competitive inhibition, KI = 3.2 μM). MSNBA does not inhibit GLUT2, GLUT1, GLUT3, GLUT4, or bacterial GlcPSe. Mutagenesis studies implicate H387 of GLUT5 in inhibitor binding near the active site.\",\n      \"method\": \"Virtual screening, proteoliposome transport assay, MCF7 cell fructose uptake, site-directed mutagenesis, ligand docking\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in proteoliposomes plus cell-based assay plus mutagenesis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27074918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fructose transport by GLUT5 shows stringent stereochemical requirement: inversion of a single stereocenter at C-3, C-4, or C-5 of fructose abolishes GLUT5-mediated transport (shifting uptake to GLUT1). 6-NBDF (all D-fructose configuration) is taken up via GLUT5; C-3, C-4, C-5 epimers are not. In silico docking with the GLUT5 crystal structure confirms stereochemical dependence.\",\n      \"method\": \"Fluorescent hexose uptake assays in breast cancer cell lines, Xenopus oocyte expression, in silico docking with GLUT5 crystal structure\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based and oocyte uptake assays with multiple stereochemical probes, single lab\",\n      \"pmids\": [\"28205432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Specific amino acid residues in GLUT5 required for fructose transport were identified using GLUT5/GLUT7 chimeras: critical positions reside in the first extracellular loop, TM5, TM7, TM8, TM9, TM10, and inter-TM loops 9-10 and 10-11. The Q167E substitution (analogous to rat Q166E) does not convert human GLUT5 into a glucose transporter but alters intracellular loop dynamics connecting TM6-7.\",\n      \"method\": \"Chimeric GLUT5/GLUT7 protein expression in NIH-3T3 cells, fructose radiotracer flux, fragment replacement analysis, molecular dynamics simulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic chimeric domain-swap analysis (26 fragments) with functional transport assay plus MD simulation, single lab\",\n      \"pmids\": [\"29259131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LXRα (NR1H3) is a transcriptional regulator of GLUT5 expression. A functional LXR response element (LXRE) was identified at -385 bp relative to the GLUT5 transcriptional start site by promoter truncation and site-directed mutagenesis. LXR agonist T0901317 increases Glut5 mRNA and protein in mouse duodenum and adipose tissue in vivo.\",\n      \"method\": \"Unbiased GLUT5 promoter screen, promoter truncation reporter assay, site-directed mutagenesis of LXRE, LXR agonist treatment in mice, qPCR, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter truncation plus mutagenesis of the LXRE plus in vivo agonist confirmation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31243309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKT1 and AKT3 activation in drug-resistant colon cancer cells causes aberrant downregulation of miR-125b-5p, leading to increased GLUT5 expression. Restoring miR-125b-5p blocked GLUT5-dependent fructose metabolism. GLUT5 silencing with siRNA attenuated mesenchymal marker expression and migratory activity in chemoresistant cells.\",\n      \"method\": \"AKT1/3 inhibition, miR-125b-5p mimic transfection, siRNA knockdown of GLUT5, migration/invasion assays, metabolite measurement\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic interventions with functional phenotype readouts, single lab\",\n      \"pmids\": [\"32649737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GLUT5 is sufficient to enable fructose-mediated cell proliferation across multiple cell types. GLUT5 overexpression in non-fructolytic cells enables growth in fructose medium; this fructose utilization occurs through glycolysis via hexokinase (HK), not ketohexokinase (KHK). Thus fructose uptake by GLUT5 is the limiting step for fructose-dependent proliferation.\",\n      \"method\": \"CRISPR-Cas9 KHK knockout, lentiviral GLUT5 overexpression in multiple cell lines, live cell imaging, Seahorse metabolic flux, LC/MS metabolomics, Crystal Violet assays\",\n      \"journal\": \"Cancer & metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell line panel, genetic KO and OE, metabolomics, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33762003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"S100P promotes SLC2A5/GLUT5 expression in colorectal cancer by binding to a specific region of the SLC2A5 promoter, reducing its methylation levels, and activating transcription. This mechanism promotes CRC cell invasion and metastasis both in vitro and in vivo.\",\n      \"method\": \"Methylation mass spectrometry sequencing, methylation-specific PCR, bisulfite sequencing PCR, ChIP-qPCR, luciferase reporter assay, intrasplenic inoculation mouse model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR plus promoter reporter assay plus methylation analysis, single lab, multiple methods\",\n      \"pmids\": [\"34188196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GLUT5 deficiency reduces GLUT5-knockout mouse colitis severity upon fructose feeding compared to overexpression, mediated by changes in colonic microbiota (reversed by antibiotics). GLUT5 controls colonic fructose levels that shape gut microbiota composition and thereby modulate colitis severity.\",\n      \"method\": \"Glut5 knockout and overexpressor transgenic mice, DSS colitis model, dietary fructose feeding, fecal microbiota analysis, broad-spectrum antibiotics treatment\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse models with mechanistic microbiota link shown by antibiotic rescue, single lab\",\n      \"pmids\": [\"34133236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-6 activates fructose uptake and fructolysis in cancer cells via STAT3-mediated transcriptional activation of GLUT5. STAT3 associates with the GLUT5 promoter region in response to IL-6. Knockdown of GLUT5 abolishes IL-6-induced fructose uptake and compromises IL-6-elicited tumor cell proliferation.\",\n      \"method\": \"IL-6 treatment, STAT3 ChIP, GLUT5 promoter binding assay, GLUT5 knockdown, fructose uptake assay, cell proliferation assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown with fructose uptake and proliferation readout, single lab\",\n      \"pmids\": [\"35813468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GLUT5-mediated fructose utilization promotes lung cancer cell migration by upregulating AKT phosphorylation via a glycolysis/lactate/AKT pathway. SLC2A5 deletion blocked migration and AKT activation; glycolysis inhibitor 2-DG and GLUT5-specific inhibitor 2,5-AM suppressed migration and AKT activation. In vivo tail-vein metastasis experiments confirmed reduced metastatic potential upon SLC2A5 deletion.\",\n      \"method\": \"CRISPR/Cas9 SLC2A5 deletion, retrovirus SLC2A5 overexpression, Transwell migration assay, Western blot for AKT phosphorylation, lactate assay, 2-DG and 2,5-AM inhibitor experiments, tail-vein metastasis mouse model\",\n      \"journal\": \"Clinical & translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus OE plus pharmacological inhibition with signaling readout in vitro and in vivo, single lab\",\n      \"pmids\": [\"36454516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9-mediated inactivation of SLC2A5 inhibits cancer cell migration and metastasis in vivo. SLC2A5-attenuated cells show dramatic alterations in mitochondrial architecture and localization, revealing a role for GLUT5 in directing mitochondrial function for cancer cell motility.\",\n      \"method\": \"CRISPR/Cas9 gene inactivation, in vitro migration assays, multiple in vivo animal metastasis models, mitochondrial imaging\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO in multiple cell lines and animal models with mitochondrial phenotype, single lab\",\n      \"pmids\": [\"36268513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Molecular dynamics simulations show GLUT5 spontaneously transitions through an occluded state resembling PfHT1, with TM7b gating helix rearrangements. D-fructose coordination lowers the energetic barriers between outward- and inward-facing states. The binding mode is consistent with biochemical analysis, and GLUT5 uses allosteric coupling of sugar binding with extracellular gate closure (via TM7b) to achieve substrate selectivity, rather than achieving high affinity through substrate-binding site alone.\",\n      \"method\": \"Enhanced sampling molecular dynamics simulations, biochemical fructose transport analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — computational structural dynamics validated by biochemical transport data, single study\",\n      \"pmids\": [\"37405832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GLUT5 physically interacts with prestin in cochlear outer hair cells. Using FRET (by FACS, acceptor photobleaching, and FLIM) and co-immunoprecipitation in HEK293T cells, both homomeric prestin-prestin and heteromeric prestin-GLUT5 interactions were demonstrated.\",\n      \"method\": \"Co-immunoprecipitation, confocal colocalization, FRET-FACS, FRET-acceptor photobleaching, FRET-FLIM in HEK293T cells\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus multiple FRET methods confirming interaction, single lab, transfected cell system\",\n      \"pmids\": [\"17443803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GLUT5 domains responsible for fructose transport were further mapped using GLUT5/GLUT3 chimeras: the GLUT5 N-terminus through TM3 and the segment between TM5 and TM11 are both necessary for fructose uptake. Chimeras lacking either region failed to transport fructose despite surface expression confirmed by biotin exofacial labeling.\",\n      \"method\": \"Chimeric GLUT5/GLUT3 protein expression in Xenopus oocytes, radiolabeled sugar uptake, exofacial biotin labeling\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic chimeric domain-swap analysis with functional uptake assay plus surface expression control, single lab\",\n      \"pmids\": [\"9492009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"d-Allulose is a substrate of GLUT5. Plasma d-allulose absorption was enhanced in fructose-pre-fed rats (with higher GLUT5 expression), and co-gavage with fructose competitively dampened d-allulose absorption. Radiotracer assay showed d-allulose inhibited D-[14C]-fructose uptake (54.8% at 50 mM), but with lower affinity than fructose itself (16.4% inhibition at 50 mM).\",\n      \"method\": \"Dietary prefeeding to modulate GLUT5, plasma allulose measurement, competitive radiotracer D-[14C]-fructose uptake assay\",\n      \"journal\": \"Food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive transport assay plus dietary GLUT5 induction as natural genetic variable, single lab\",\n      \"pmids\": [\"30502192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNAI1 and SNAI2 transcription factors repress SLC2A5/GLUT5 expression. Trichostatin A (HDAC inhibitor) induces SNAI1/SNAI2 expression, which in turn suppresses SLC2A5 transcription and sensitizes colon cancer cells to cisplatin and oxaliplatin.\",\n      \"method\": \"SNAI1/SNAI2 overexpression, trichostatin A treatment, RT-PCR, Western blot, cell viability assays\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcription factor overexpression with mRNA/protein readout, pharmacological HDAC inhibitor, single lab\",\n      \"pmids\": [\"37062501\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC2A5/GLUT5 is a 12-transmembrane major facilitator superfamily fructose transporter that uses a gated-pore rocker-switch mechanism (with critical roles for TM7 and TM10 helices) to mediate facilitated diffusion of D-fructose (Km ~6–15 mM depending on species) but not glucose; its substrate selectivity is determined by specific residues in TM5, TM7–TM10, and extracellular loops (with a single point mutation sufficient to switch fructose-to-glucose preference), and its expression is transcriptionally regulated by luminal fructose (via glucocorticoid receptor nuclear translocation, histone H3/H4 acetylation at the Glut5 promoter, and cAMP/mRNA stabilization), thyroid hormone receptors, LXRα, STAT3 (downstream of IL-6), and AKT/miR-125b-5p signaling, while being constitutively localized at the plasma membrane independently of insulin; GLUT5 is required for intestinal fructose absorption, renal proximal tubule fructose reuptake, and adipocyte/skeletal muscle fructose utilization, and its overexpression in cancer cells enables fructose-dependent proliferation and metastasis via glycolysis/AKT activation and mitochondrial remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC2A5/GLUT5 is a plasma-membrane fructose transporter of the major facilitator superfamily that mediates cytochalasin B-insensitive, high-affinity facilitated diffusion of D-fructose (Km ~6\\u201315 mM) but not glucose, providing the rate-limiting entry step for fructose into intestinal, renal, muscle, adipocyte, and erythrocyte tissues [#0, #4, #10, #11]. Crystal structures captured in outward- and inward-facing states reveal a rocker-switch transport cycle gated by local rearrangements of the TM7 and TM10 helices, and a single point mutation is sufficient to switch GLUT5 substrate preference between fructose and glucose, defining how a small set of residues across the first extracellular loop, TM5, and TM7\\u2013TM10 dictates strict fructose selectivity and furanose-form, stereochemically defined recognition [#28, #30, #33, #32]. GLUT5 localizes constitutively to the apical brush-border membrane of enterocytes and renal proximal tubule cells and to the sarcolemma and adipocyte plasma membrane independently of insulin-stimulated translocation [#1, #16, #14, #3]. Its expression is induced specifically by luminal fructose through a transcriptional and post-transcriptional program involving glucocorticoid receptor nuclear translocation and binding to the Glut5 promoter, histone H3 acetylation and Pol II recruitment, thyroid hormone receptor and LXR\\u03b1 response elements, and cAMP-dependent mRNA stabilization [#15, #27, #24, #17, #34, #21]. Physiologically, GLUT5 is required for intestinal fructose absorption and feed-forward induction of fructolytic enzymes upstream of ketohexokinase, and its loss prevents fructose-induced hypertension and alters microbiota-dependent colitis [#29, #25, #38]. In cancer, GLUT5-mediated fructose uptake is sufficient to support fructose-dependent proliferation through hexokinase-driven glycolysis and drives migration and metastasis via a glycolysis/lactate/AKT axis and mitochondrial remodeling, with its expression controlled by IL-6/STAT3, AKT/miR-125b-5p, S100P-mediated promoter demethylation, and SNAI1/SNAI2 repression [#36, #40, #41, #39, #35, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the fundamental identity of GLUT5 as a fructose-selective transporter, distinguishing it functionally from the glucose-transporting GLUTs.\",\n      \"evidence\": \"Heterologous expression of human GLUT5 in Xenopus oocytes with radiolabeled sugar uptake and cytochalasin B inhibition studies\",\n      \"pmids\": [\"1634504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of fructose selectivity\", \"Did not address tissue-specific physiological roles\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defined where GLUT5 acts in tissue, showing apical brush-border localization in enterocytes and developmental regulation of its targeting.\",\n      \"evidence\": \"Immunohistochemistry and Western blot of purified brush-border membranes from adult and fetal human intestine\",\n      \"pmids\": [\"1550217\", \"1530566\", \"1397712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of apical targeting not defined\", \"Whether basolateral pools exist not resolved at this stage\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Showed GLUT5 is a constitutive, non-insulin-responsive transporter, contrasting it with insulin-regulated GLUT4.\",\n      \"evidence\": \"Subcellular fractionation of adipocytes with/without insulin plus cytochalasin B photolabeling\",\n      \"pmids\": [\"1397712\", \"9686924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab fractionation\", \"Did not exclude longer-term transcriptional insulin effects later observed in muscle\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Began mapping the protein determinants of fructose transport using chimeric transporters, localizing function to the N-terminal half and C-terminal region.\",\n      \"evidence\": \"GLUT1/GLUT5 and GLUT5/GLUT3 chimeric protein expression in CHO cells and oocytes with sugar uptake assays\",\n      \"pmids\": [\"7588216\", \"9492009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution limited to large domains, not individual residues\", \"No structural model available\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Refined the substrate-recognition profile, showing GLUT5 transports D-fructose in the furanose form across a broad pH range.\",\n      \"evidence\": \"Xenopus oocyte expression with sugar analogue inhibition and pH variation\",\n      \"pmids\": [\"9299540\", \"7980458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residues mediating furanose recognition not identified\", \"No co-structure with substrate\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that luminal fructose, not endocrine signals, drives intestinal GLUT5 induction, establishing substrate-sensing as the regulatory input.\",\n      \"evidence\": \"Thiry-Vella intestinal bypass surgery in weaning rats with transport and Northern blot readout\",\n      \"pmids\": [\"9486174\", \"9124564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor of luminal fructose not identified\", \"Did not connect signal to specific promoter elements\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved a post-transcriptional arm of GLUT5 regulation, linking cAMP to GLUT5 mRNA stability via 3'-UTR RNA-protein complexes.\",\n      \"evidence\": \"mRNA half-life measurement, PKA inhibition, RNA-protein binding assays identifying Paip2 in Caco-2 cells\",\n      \"pmids\": [\"12820898\", \"8037665\", \"8554516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional role of Paip2 in destabilization not validated by depletion\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected fructose sensing to the chromatin level, showing GR nuclear translocation, promoter binding, and histone acetylation drive developmental GLUT5 induction.\",\n      \"evidence\": \"ChIP for Pol II, GR, and histone acetylation marks in perfused rat intestine of defined ages\",\n      \"pmids\": [\"21222652\", \"17947353\", \"18556366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fructose signal reaches GR not defined\", \"Histone acetyltransferase responsible not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the atomic-resolution mechanism, capturing outward- and inward-facing states and showing a single residue switches fructose-versus-glucose preference.\",\n      \"evidence\": \"X-ray crystallography of rat and bovine GLUT5 in two conformations plus point-mutation functional analysis\",\n      \"pmids\": [\"26416735\", \"26306809\", \"29259131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate-bound human structure\", \"Conformational transition dynamics inferred, not directly observed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed GLUT5 upstream in a feed-forward fructose-sensing pathway required for fructolytic and gluconeogenic enzyme induction.\",\n      \"evidence\": \"GLUT5-KO, KHK-KO, and Rab11a-KO mice with dietary fructose gavage and gene expression readout\",\n      \"pmids\": [\"26084694\", \"18496516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the intracellular fructose-sensing signal not pinned down\", \"Tissue specificity of feed-forward loop beyond intestine unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the transcriptional control network by identifying functional thyroid hormone receptor and LXR\\u03b1 response elements in the GLUT5 promoter.\",\n      \"evidence\": \"Promoter truncation and mutagenesis reporter assays, EMSA, and in vivo agonist treatment in mice\",\n      \"pmids\": [\"31243309\", \"10191252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of multiple promoter inputs not modeled\", \"Physiological context where each factor dominates unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated GLUT5-mediated fructose uptake is the limiting and sufficient step for fructose-dependent cancer cell proliferation, routed through hexokinase rather than ketohexokinase.\",\n      \"evidence\": \"Lentiviral GLUT5 overexpression and KHK CRISPR-KO across multiple cell lines with metabolic flux and metabolomics\",\n      \"pmids\": [\"33762003\", \"32649737\", \"34188196\", \"35813468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type determinants of HK-versus-KHK routing not fully defined\", \"In vivo tumor dependence on dietary fructose not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked GLUT5 fructose metabolism to malignant migration and metastasis via a glycolysis/lactate/AKT axis and mitochondrial remodeling.\",\n      \"evidence\": \"CRISPR SLC2A5 deletion plus overexpression with migration assays, AKT phosphorylation, pharmacological inhibition, and tail-vein metastasis models\",\n      \"pmids\": [\"36454516\", \"36268513\", \"32649737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking fructose metabolism to mitochondrial architecture not resolved\", \"Single lab for each model system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a dynamic mechanistic refinement, showing fructose binding lowers transition barriers and that allosteric TM7b gating, not the binding site alone, confers selectivity.\",\n      \"evidence\": \"Enhanced-sampling molecular dynamics simulations validated against biochemical transport data\",\n      \"pmids\": [\"37405832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational prediction lacks direct structural snapshot of the occluded state\", \"Human transporter dynamics inferred from model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple promoter inputs (GR, THR, LXR\\u03b1, STAT3, S100P, SNAI1/2), post-transcriptional control, and the luminal fructose-sensing signal are integrated to set GLUT5 levels in a given cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of combinatorial GLUT5 transcriptional regulation\", \"The proximal fructose sensor upstream of these factors is unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 4, 6, 8, 10, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 3, 7, 14, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 4, 25, 29]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [29, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [36, 40, 41]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLC26A6\", \"prestin\", \"PAIP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}