{"gene":"SLC6A19","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2004,"finding":"SLC6A19 (B0AT1) encodes a sodium-dependent, chloride-independent neutral amino acid transporter expressed predominantly in kidney and intestine; disease-causing mutations reduce neutral amino acid transport function in vitro, establishing it as the gene mutated in Hartnup disorder.","method":"Positional cloning, mutation identification, in vitro transport assays in heterologous expression systems","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — two independent labs simultaneously confirmed causative mutations and functional loss of transport, replicated with multiple orthogonal methods","pmids":["15286787","15286788"],"is_preprint":false},{"year":2005,"finding":"Mouse B0AT1 mediates electrogenic Na+-amino acid co-transport with 1:1 stoichiometry; all neutral amino acids are substrates but large neutral non-aromatic amino acids are preferred; no other ions are involved in the transport mechanism; a random binding order model with a positive charge on the ternary [Na+-substrate-transporter] complex is consistent with experimental data.","method":"Two-electrode voltage-clamp and tracer studies in Xenopus oocyte expression system","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — detailed electrophysiological reconstitution with kinetic modeling, replicated independently","pmids":["15804236"],"is_preprint":false},{"year":2005,"finding":"Mouse B0AT1 transports one Na+ per neutral amino acid via an ordered, simultaneous mechanism in which the amino acid binds prior to Na+, followed by simultaneous translocation; Li+ can partially substitute for Na+; Cl- and H+ influence current magnitude.","method":"Two-electrode voltage-clamp with simultaneous charge translocation and radiolabeled amino acid uptake measurements in Xenopus oocytes","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — simultaneous electrophysiology and isotope flux in the same cell, rigorous kinetic analysis, single lab","pmids":["16133263"],"is_preprint":false},{"year":2009,"finding":"SLC6A19 requires either collectrin (TMEM27) or angiotensin-converting enzyme 2 (ACE2) for surface expression in the kidney and intestine, respectively.","method":"Heterologous expression in Xenopus oocytes and cell lines with co-expression of ancillary proteins; review synthesizing experimental findings","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review citing established experimental co-expression data; original experiments from multiple labs","pmids":["19472175"],"is_preprint":false},{"year":2010,"finding":"SGK1, SGK2, and SGK3 stimulate SLC6A19 transport activity by increasing cell surface expression of the transporter (higher Vmax without changing substrate affinity); SGK stabilizes the transporter in the plasma membrane rather than increasing insertion rate; ACE2 co-expression markedly increases SLC6A19 currents and is further enhanced by SGK isoforms.","method":"Two-electrode voltage-clamp in Xenopus oocytes, quantitative immunoassay for surface protein, brefeldin A insertion-block experiments","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, surface quantification, BFA block) in single lab","pmids":["20511718"],"is_preprint":false},{"year":2011,"finding":"Mice lacking B0AT1 (Slc6a19-/-) show complete abolition of Na+-dependent neutral amino acid uptake in intestinal and renal brush-border membrane vesicles; these mice exhibit reduced body weight, blunted postprandial insulin secretion, reduced intestinal mTOR pathway signaling, and activation of the GCN2/ATF4 stress response pathway, demonstrating that epithelial neutral amino acid uptake is essential for body weight regulation and nutrient signaling.","method":"Slc6a19 knockout mouse model; brush-border membrane vesicle transport assays; insulin secretion measurements; mTOR and GCN2/ATF4 pathway analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple defined molecular and physiological phenotypes, brush-border transport directly measured","pmids":["21636576"],"is_preprint":false},{"year":2011,"finding":"JAK2 (and gain-of-function V617F-JAK2) stimulates SLC6A19 transport activity by increasing carrier protein abundance at the cell membrane (higher Vmax, unchanged affinity); kinase-dead K882E-JAK2 has no effect; JAK2 stimulates transporter insertion into rather than inhibiting retrieval from the plasma membrane.","method":"Two-electrode voltage-clamp in Xenopus oocytes, chemiluminescence surface protein quantification, brefeldin A insertion-block experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including kinase-dead control, single lab","pmids":["21964291"],"is_preprint":false},{"year":2012,"finding":"B0AT1 forms functional complexes with the peptidases aminopeptidase N (APN/CD13) and ACE2 in intestinal brush-border membranes; APN increases B0AT1 substrate affinity up to 2.5-fold and increases surface expression; site-directed mutagenesis of APN's catalytic site suggests it increases local substrate concentration to modulate apparent affinity.","method":"Co-immunoprecipitation and Blue native electrophoresis of intestinal brush-border membrane proteins; Xenopus oocyte co-expression electrophysiology; site-directed mutagenesis of APN","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal co-IP plus functional reconstitution in oocytes plus mutagenesis, single lab with multiple orthogonal methods","pmids":["22677001"],"is_preprint":false},{"year":2012,"finding":"PKB/Akt stimulates SLC6A19 transport activity by increasing maximal transport rate (Vmax) without altering substrate affinity; this effect is augmented by PIKfyve in a PKB/Akt phosphorylation-dependent manner; PKB/Akt promotes transporter insertion into the plasma membrane rather than inhibiting retrieval.","method":"Two-electrode voltage-clamp in Xenopus oocytes with wild-type and inactive mutant kinases; brefeldin A insertion-block experiments","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead controls and BFA experiments, single lab","pmids":["23234856"],"is_preprint":false},{"year":2013,"finding":"Slc6a19 gene expression in intestinal enterocytes is regulated at three levels: CpG dinucleotides in the proximal promoter are highly methylated in crypt cells and fully demethylated in villus cells; histone H3K27Ac (active promoter mark) is present in villus but not crypt cells; transcription factors HNF1a and HNF4a activate transcription in villus enterocytes while SOX9 represses expression in crypts.","method":"Fractionation of crypt vs villus enterocytes; bisulfite sequencing for DNA methylation; ChIP for H3K27Ac; gene expression analysis with transcription factor manipulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal epigenetic and transcriptional methods, single lab","pmids":["24121511"],"is_preprint":false},{"year":2014,"finding":"Nimesulide is a potent inhibitor of B0AT1 (IC50 ~23 μM in proteoliposomes); it shows noncompetitive inhibition with respect to glutamine but competitive inhibition with respect to Na+; molecular docking suggests nimesulide binds an external site on B0AT1, sterically blocking the translocation path.","method":"Proteoliposome Na+-[3H]glutamine co-transport assay; inhibition kinetics analysis; molecular docking using B0AT1 homology model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transport inhibition kinetics in reconstituted proteoliposomes plus computational docking, single lab","pmids":["24704252"],"is_preprint":false},{"year":2015,"finding":"Collectrin is necessary for both plasma membrane expression and catalytic function of B0AT1 and B0AT3; syntaxin 1A and syntaxin 3 inhibit B0AT1 membrane expression by competing with collectrin; mutagenesis screening identified residues on transmembrane domains 1α, 5, and 7 on one face of B0AT3 as key for collectrin interaction, with distinct residues mediating membrane expression vs. catalytic activation.","method":"Monocarboxylate-B0AT1/3 fusion constructs in Xenopus oocytes; mutagenesis screening; electrophysiology and surface expression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis plus functional reconstitution identifying specific interaction residues, multiple orthogonal readouts, single lab","pmids":["26240152"],"is_preprint":false},{"year":2021,"finding":"Each [ACE2:B0AT1] heterodimer constitutes a functional unit for Na+-dependent neutral amino acid transport in situ; radiation inactivation analysis of brush-border membrane vesicles yielded a functional unit molecular weight of 183.7 ± 16.8 kDa, consistent with one ACE2:B0AT1 heterodimer acting as the transport unit within the larger ~345 kDa dimer-of-heterodimers quaternary complex.","method":"Radiation inactivation analysis using high-energy electron radiation from a linear accelerator on purified enterocyte brush-border membrane vesicles; target theory molecular weight calculation","journal":"Function (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — novel physical approach in native membranes but single lab, single method","pmids":["34847569"],"is_preprint":false},{"year":2022,"finding":"B0AT1 is expressed in mouse preimplantation embryos along with ACE2; B0AT1 knockout mice show decreased fertility and reduced preimplantation embryo development; B0AT1 mediates the majority of L-proline uptake at the 4-8 cell stage; transport competition experiments confirm B0AT1 substrate specificity in embryos.","method":"Slc6a19 knockout mouse; radiolabeled L-proline uptake in oocytes and embryos; competition assays with unlabeled amino acids","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with direct radiolabel transport assay, competition experiments, single lab","pmids":["36611813"],"is_preprint":false},{"year":2025,"finding":"Nine Hartnup disease-causing B0AT1 variants (R57C, G93R, R95P, R178Q, L242P, G284R, S303L, D517G, P579L) are retained in the endoplasmic reticulum and fail to traffic to the plasma membrane; ER-retained variants R178Q and S303L also significantly disrupt ACE2 intracellular trafficking and its localization to the plasma membrane.","method":"Subcellular localization assays (biochemical fractionation and immunofluorescence) of 18 B0AT1 variants; in silico analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic evaluation of 18 variants with biochemical localization assays, identifies ER quality control as mechanism, single lab","pmids":["40852587"],"is_preprint":false},{"year":2025,"finding":"SLC6A19 transports tryptophan into renal cell carcinoma cells, facilitating de novo NAD+ biosynthesis which activates SIRT1; SIRT1 deacetylates histone H3K27, repressing NF-κB p65 transcription and suppressing epithelial-mesenchymal transition; KLF4 inactivation is identified as the key factor for low SLC6A19 expression in RCC cells.","method":"Overexpression of SLC6A19 in RCC cells; in vitro and in vivo proliferation/migration/invasion assays; NAD+ measurement; SIRT1 activity assay; H3K27 acetylation ChIP; NF-κB pathway analysis; KLF4 transcription factor binding assays","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway assays in single lab, mechanistic chain established by overexpression with multiple molecular readouts","pmids":["41203631"],"is_preprint":false}],"current_model":"SLC6A19 (B0AT1) is a sodium-dependent, chloride-independent electrogenic transporter that co-transports neutral amino acids with Na+ in a 1:1 stoichiometry at the apical membrane of intestinal enterocytes and renal proximal tubule cells; it requires ancillary proteins (ACE2 in intestine, collectrin/TMEM27 in kidney) for plasma membrane trafficking and full catalytic activity, forms functional digestive complexes with peptidases APN and ACE2 that modulate its substrate affinity and surface expression, and its activity is up-regulated by kinases SGK1-3, PKB/Akt (via PIKfyve), and JAK2 through increased transporter insertion into the plasma membrane; loss-of-function mutations cause Hartnup disorder via ER retention and impaired trafficking, and its absence in mice abolishes epithelial neutral amino acid uptake, impairs mTOR signaling and insulin secretion, and reduces body weight."},"narrative":{"mechanistic_narrative":"SLC6A19 (B0AT1) is the principal apical, sodium-dependent, chloride-independent transporter that drives bulk reabsorption and absorption of neutral amino acids in renal proximal tubule and intestinal enterocytes, and its loss-of-function mutations cause Hartnup disorder [PMID:15286787, PMID:15286788]. It mediates electrogenic Na+:amino acid co-transport with 1:1 stoichiometry through an ordered mechanism in which the amino acid binds before Na+, accepting all neutral amino acids with preference for large non-aromatic substrates [PMID:15804236, PMID:16133263]. Catalytically competent surface expression requires tissue-specific ancillary partners — collectrin (TMEM27) in kidney and ACE2 in intestine — with collectrin contacting transmembrane faces that separately govern membrane delivery and catalytic activation [PMID:19472175, PMID:26240152]. At the intestinal brush border B0AT1 assembles into functional digestive complexes with the peptidases aminopeptidase N and ACE2, where APN raises apparent substrate affinity and surface expression, and a single ACE2:B0AT1 heterodimer constitutes the minimal transport unit within a larger dimer-of-heterodimers assembly [PMID:22677001, PMID:34847569]. Transport activity is acutely up-regulated by kinases SGK1-3, PKB/Akt (via PIKfyve), and JAK2, all increasing transporter abundance at the plasma membrane without changing affinity [PMID:20511718, PMID:21964291, PMID:23234856]. Genetic ablation in mice abolishes epithelial neutral amino acid uptake and reduces body weight, postprandial insulin secretion, and intestinal mTOR signaling while activating the GCN2/ATF4 stress response, establishing the transporter as essential for systemic nutrient sensing [PMID:21636576]. Hartnup-causing variants act through endoplasmic reticulum retention and failure to reach the plasma membrane, with some variants additionally disrupting ACE2 trafficking [PMID:40852587].","teleology":[{"year":2004,"claim":"Established the molecular identity of the long-sought intestinal/renal neutral amino acid transporter and tied it directly to a human Mendelian disease.","evidence":"Positional cloning, mutation identification, and in vitro transport assays in heterologous systems","pmids":["15286787","15286788"],"confidence":"High","gaps":["Transport mechanism and stoichiometry not yet resolved","Ancillary requirements for surface expression unknown"]},{"year":2005,"claim":"Defined the biophysical transport mechanism, answering how ion coupling and substrate order produce electrogenic uptake.","evidence":"Two-electrode voltage-clamp with simultaneous charge and radiolabeled amino acid flux in Xenopus oocytes; kinetic modeling","pmids":["15804236","16133263"],"confidence":"High","gaps":["Discrepancy between random-order and ordered binding models across the two studies","Structural basis of the translocation cycle not determined"]},{"year":2009,"claim":"Identified tissue-specific ancillary proteins required for surface delivery, explaining why the transporter functions differently in kidney versus intestine.","evidence":"Heterologous co-expression of collectrin/TMEM27 and ACE2 in oocytes and cell lines (review synthesis)","pmids":["19472175"],"confidence":"Medium","gaps":["Molecular interaction interface not mapped","Review-level synthesis rather than single primary dataset"]},{"year":2010,"claim":"Showed acute kinase regulation by SGK isoforms acts by stabilizing transporter at the membrane rather than altering catalysis.","evidence":"Voltage-clamp, surface protein quantification, and brefeldin A insertion-block in oocytes","pmids":["20511718"],"confidence":"Medium","gaps":["Direct phosphorylation site on SLC6A19 not identified","Physiological context of SGK regulation untested in vivo"]},{"year":2011,"claim":"JAK2 was added as a regulator acting through increased transporter insertion, with a kinase-dead control establishing catalytic dependence.","evidence":"Voltage-clamp, chemiluminescence surface quantification, BFA block, K882E kinase-dead mutant in oocytes","pmids":["21964291"],"confidence":"Medium","gaps":["Direct substrate phosphorylation not shown","Relevance to JAK2-V617F disease states unexplored"]},{"year":2011,"claim":"Established the systemic physiological consequence of losing the transporter, linking epithelial amino acid uptake to body weight, insulin secretion, and nutrient signaling.","evidence":"Slc6a19 knockout mouse with brush-border vesicle transport assays, insulin measurements, and mTOR/GCN2-ATF4 pathway analysis","pmids":["21636576"],"confidence":"High","gaps":["Tissue-specific contributions to phenotype not dissected","Mechanism connecting transport loss to mTOR not resolved at molecular level"]},{"year":2012,"claim":"Revealed that the transporter operates within a brush-border digestive complex where peptidases shape its kinetic behavior.","evidence":"Reciprocal co-IP and blue-native electrophoresis of brush-border membranes, oocyte co-expression, APN catalytic-site mutagenesis","pmids":["22677001"],"confidence":"High","gaps":["Stoichiometry of the multi-protein complex not defined here","In vivo physiological role of APN coupling untested"]},{"year":2012,"claim":"Extended kinase regulation to PKB/Akt acting cooperatively with PIKfyve to promote membrane insertion.","evidence":"Voltage-clamp with wild-type and inactive kinase mutants plus BFA block in oocytes","pmids":["23234856"],"confidence":"Medium","gaps":["Direct phosphorylation target unidentified","Single lab, oocyte-only system"]},{"year":2013,"claim":"Defined how spatial expression along the crypt-villus axis is set, integrating DNA methylation, histone marks, and transcription factors.","evidence":"Crypt/villus fractionation, bisulfite sequencing, H3K27Ac ChIP, and HNF1a/HNF4a/SOX9 manipulation","pmids":["24121511"],"confidence":"Medium","gaps":["Upstream signals controlling these epigenetic states unknown","Conservation of regulation in human tissue untested"]},{"year":2014,"claim":"Provided a pharmacological tool and inhibitor binding model, supporting an external blocking site on the translocation path.","evidence":"Proteoliposome Na+-glutamine co-transport inhibition kinetics and molecular docking with a homology model","pmids":["24704252"],"confidence":"Medium","gaps":["Inhibitor binding site not experimentally validated","Docking based on homology model lacking experimental structure"]},{"year":2015,"claim":"Mapped specific collectrin-interacting residues and showed membrane delivery and catalytic activation are separable functions.","evidence":"Fusion constructs, mutagenesis screening, electrophysiology, and surface expression in oocytes; syntaxin competition","pmids":["26240152"],"confidence":"High","gaps":["Structural detail of the collectrin contact face not solved","Syntaxin regulation in native epithelium untested"]},{"year":2021,"claim":"Determined the functional transport unit in native membranes, showing one ACE2:B0AT1 heterodimer suffices within the larger assembly.","evidence":"Radiation inactivation analysis of enterocyte brush-border membrane vesicles with target-theory mass calculation","pmids":["34847569"],"confidence":"Medium","gaps":["Single method and single lab","Role of the higher-order dimer-of-heterodimers in function unclear"]},{"year":2022,"claim":"Extended the transporter's role beyond epithelia, showing it supplies proline to early embryos and supports fertility.","evidence":"Slc6a19 knockout mouse with radiolabeled L-proline uptake and amino acid competition assays in embryos","pmids":["36611813"],"confidence":"Medium","gaps":["Mechanism linking proline uptake to embryo development not defined","Human relevance of embryonic expression untested"]},{"year":2025,"claim":"Clarified the molecular pathology of Hartnup variants as ER retention, and showed some variants impair ACE2 trafficking.","evidence":"Subcellular localization assays and in silico analysis of 18 disease variants","pmids":["40852587"],"confidence":"Medium","gaps":["Whether ER retention is rescuable not addressed","Functional consequence of ACE2 mistrafficking not quantified"]},{"year":2025,"claim":"Implicated the transporter in cancer biology via tryptophan-fueled NAD+/SIRT1 signaling that suppresses EMT in renal carcinoma.","evidence":"SLC6A19 overexpression in RCC cells with NAD+ measurement, SIRT1 activity, H3K27ac ChIP, NF-kB and KLF4 analyses","pmids":["41203631"],"confidence":"Medium","gaps":["Causal chain rests on overexpression rather than endogenous modulation","Generalizability beyond RCC unknown"]},{"year":null,"claim":"An experimentally determined high-resolution structure of the transport cycle and a unifying model reconciling ordered versus random substrate binding remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental structure of the human transporter in the corpus","Direct phosphorylation sites underlying kinase regulation unidentified","In vivo significance of kinase regulation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,5,13]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4,6,8,11,12]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-8963743","term_label":"Digestion and absorption","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,14]}],"complexes":["ACE2:B0AT1 heterodimer (dimer-of-heterodimers)","B0AT1-APN-ACE2 brush-border digestive complex","collectrin (TMEM27):B0AT1 complex"],"partners":["ACE2","TMEM27","APN","SGK1","JAK2","AKT1","STX1A","STX3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q695T7","full_name":"Sodium-dependent neutral amino acid transporter B(0)AT1","aliases":["Solute carrier family 6 member 19","System B(0) neutral amino acid transporter AT1"],"length_aa":634,"mass_kda":71.1,"function":"Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells (PubMed:15286787, PubMed:15286788, PubMed:18424768, PubMed:18484095, PubMed:19185582, PubMed:26240152). This uptake is sodium-dependent and chloride-independent (PubMed:15286787, PubMed:15286788, PubMed:19185582). Requires CLTRN in kidney or ACE2 in intestine for cell surface expression and amino acid transporter activity (PubMed:18424768, PubMed:19185582)","subcellular_location":"Cell membrane; Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/Q695T7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC6A19","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC6A19","total_profiled":1310},"omim":[{"mim_id":"610300","title":"SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER), MEMBER 18; SLC6A18","url":"https://www.omim.org/entry/610300"},{"mim_id":"608893","title":"SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER), MEMBER 19; SLC6A19","url":"https://www.omim.org/entry/608893"},{"mim_id":"608331","title":"SOLUTE CARRIER FAMILY 36 (PROTON/AMINO ACID SYMPORTER), MEMBER 2; SLC36A2","url":"https://www.omim.org/entry/608331"},{"mim_id":"605616","title":"SOLUTE CARRIER FAMILY 6 (PROLINE IMINO TRANSPORTER), MEMBER 20; SLC6A20","url":"https://www.omim.org/entry/605616"},{"mim_id":"300335","title":"ANGIOTENSIN I-CONVERTING ENZYME 2; ACE2","url":"https://www.omim.org/entry/300335"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":134.2},{"tissue":"kidney","ntpm":82.9}],"url":"https://www.proteinatlas.org/search/SLC6A19"},"hgnc":{"alias_symbol":["B0AT1"],"prev_symbol":[]},"alphafold":{"accession":"Q695T7","domains":[{"cath_id":"-","chopping":"12-611","consensus_level":"medium","plddt":92.1522,"start":12,"end":611}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q695T7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q695T7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q695T7-F1-predicted_aligned_error_v6.png","plddt_mean":90.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC6A19","jax_strain_url":"https://www.jax.org/strain/search?query=SLC6A19"},"sequence":{"accession":"Q695T7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q695T7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q695T7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q695T7"}},"corpus_meta":[{"pmid":"15286787","id":"PMC_15286787","title":"Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15286787","citation_count":212,"is_preprint":false},{"pmid":"15286788","id":"PMC_15286788","title":"Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15286788","citation_count":185,"is_preprint":false},{"pmid":"15804236","id":"PMC_15804236","title":"Characterization of mouse amino acid transporter B0AT1 (slc6a19).","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15804236","citation_count":106,"is_preprint":false},{"pmid":"19472175","id":"PMC_19472175","title":"The role of the neutral amino acid transporter B0AT1 (SLC6A19) in Hartnup disorder and protein nutrition.","date":"2009","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/19472175","citation_count":73,"is_preprint":false},{"pmid":"21636576","id":"PMC_21636576","title":"Impaired nutrient signaling and body weight control in a Na+ neutral amino acid cotransporter (Slc6a19)-deficient mouse.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21636576","citation_count":69,"is_preprint":false},{"pmid":"16133263","id":"PMC_16133263","title":"Steady-state kinetic characterization of the mouse B(0)AT1 sodium-dependent neutral amino acid transporter.","date":"2005","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16133263","citation_count":55,"is_preprint":false},{"pmid":"20511718","id":"PMC_20511718","title":"The serum and glucocorticoid inducible kinases SGK1-3 stimulate the neutral amino acid transporter SLC6A19.","date":"2010","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20511718","citation_count":52,"is_preprint":false},{"pmid":"22677001","id":"PMC_22677001","title":"Intestinal peptidases form functional complexes with the neutral amino acid transporter B(0)AT1.","date":"2012","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/22677001","citation_count":51,"is_preprint":false},{"pmid":"28915252","id":"PMC_28915252","title":"Expression and regulation of the neutral amino acid transporter B0AT1 in rat small intestine.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28915252","citation_count":47,"is_preprint":false},{"pmid":"28176326","id":"PMC_28176326","title":"Identification of novel inhibitors of the amino acid transporter B0 AT1 (SLC6A19), a potential target to induce protein restriction and to treat type 2 diabetes.","date":"2017","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28176326","citation_count":47,"is_preprint":false},{"pmid":"26240152","id":"PMC_26240152","title":"Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26240152","citation_count":41,"is_preprint":false},{"pmid":"20448142","id":"PMC_20448142","title":"Luminal leptin inhibits L-glutamine transport in rat small intestine: involvement of ASCT2 and B0AT1.","date":"2010","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20448142","citation_count":37,"is_preprint":false},{"pmid":"23234856","id":"PMC_23234856","title":"Up-regulation of amino acid transporter SLC6A19 activity and surface protein abundance by PKB/Akt and PIKfyve.","date":"2012","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23234856","citation_count":35,"is_preprint":false},{"pmid":"35979966","id":"PMC_35979966","title":"Aristolochic acid-induced nephropathy is attenuated in mice lacking the neutral amino acid transporter B0AT1 (Slc6a19).","date":"2022","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35979966","citation_count":29,"is_preprint":false},{"pmid":"24704252","id":"PMC_24704252","title":"Nimesulide binding site in the B0AT1 (SLC6A19) amino acid transporter. Mechanism of inhibition revealed by proteoliposome transport assay and molecular modelling.","date":"2014","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24704252","citation_count":28,"is_preprint":false},{"pmid":"31470570","id":"PMC_31470570","title":"Mice Lacking the Intestinal and Renal Neutral Amino Acid Transporter SLC6A19 Demonstrate the Relationship between Dietary Protein Intake and Amino Acid Malabsorption.","date":"2019","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/31470570","citation_count":27,"is_preprint":false},{"pmid":"20399395","id":"PMC_20399395","title":"Novel mutation in SLC6A19 causing late-onset seizures in Hartnup disorder.","date":"2010","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20399395","citation_count":25,"is_preprint":false},{"pmid":"24121511","id":"PMC_24121511","title":"Enterocyte-specific regulation of the apical nutrient transporter SLC6A19 (B(0)AT1) by transcriptional and epigenetic 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SLC6A20","date":"2025-07-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.07.663433","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26830,"output_tokens":4016,"usd":0.070365,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11965,"output_tokens":4254,"usd":0.083087,"stage2_stop_reason":"end_turn"},"total_usd":0.153452,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"SLC6A19 (B0AT1) encodes a sodium-dependent, chloride-independent neutral amino acid transporter expressed predominantly in kidney and intestine; disease-causing mutations reduce neutral amino acid transport function in vitro, establishing it as the gene mutated in Hartnup disorder.\",\n      \"method\": \"Positional cloning, mutation identification, in vitro transport assays in heterologous expression systems\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — two independent labs simultaneously confirmed causative mutations and functional loss of transport, replicated with multiple orthogonal methods\",\n      \"pmids\": [\"15286787\", \"15286788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse B0AT1 mediates electrogenic Na+-amino acid co-transport with 1:1 stoichiometry; all neutral amino acids are substrates but large neutral non-aromatic amino acids are preferred; no other ions are involved in the transport mechanism; a random binding order model with a positive charge on the ternary [Na+-substrate-transporter] complex is consistent with experimental data.\",\n      \"method\": \"Two-electrode voltage-clamp and tracer studies in Xenopus oocyte expression system\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — detailed electrophysiological reconstitution with kinetic modeling, replicated independently\",\n      \"pmids\": [\"15804236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse B0AT1 transports one Na+ per neutral amino acid via an ordered, simultaneous mechanism in which the amino acid binds prior to Na+, followed by simultaneous translocation; Li+ can partially substitute for Na+; Cl- and H+ influence current magnitude.\",\n      \"method\": \"Two-electrode voltage-clamp with simultaneous charge translocation and radiolabeled amino acid uptake measurements in Xenopus oocytes\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — simultaneous electrophysiology and isotope flux in the same cell, rigorous kinetic analysis, single lab\",\n      \"pmids\": [\"16133263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLC6A19 requires either collectrin (TMEM27) or angiotensin-converting enzyme 2 (ACE2) for surface expression in the kidney and intestine, respectively.\",\n      \"method\": \"Heterologous expression in Xenopus oocytes and cell lines with co-expression of ancillary proteins; review synthesizing experimental findings\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review citing established experimental co-expression data; original experiments from multiple labs\",\n      \"pmids\": [\"19472175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SGK1, SGK2, and SGK3 stimulate SLC6A19 transport activity by increasing cell surface expression of the transporter (higher Vmax without changing substrate affinity); SGK stabilizes the transporter in the plasma membrane rather than increasing insertion rate; ACE2 co-expression markedly increases SLC6A19 currents and is further enhanced by SGK isoforms.\",\n      \"method\": \"Two-electrode voltage-clamp in Xenopus oocytes, quantitative immunoassay for surface protein, brefeldin A insertion-block experiments\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, surface quantification, BFA block) in single lab\",\n      \"pmids\": [\"20511718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mice lacking B0AT1 (Slc6a19-/-) show complete abolition of Na+-dependent neutral amino acid uptake in intestinal and renal brush-border membrane vesicles; these mice exhibit reduced body weight, blunted postprandial insulin secretion, reduced intestinal mTOR pathway signaling, and activation of the GCN2/ATF4 stress response pathway, demonstrating that epithelial neutral amino acid uptake is essential for body weight regulation and nutrient signaling.\",\n      \"method\": \"Slc6a19 knockout mouse model; brush-border membrane vesicle transport assays; insulin secretion measurements; mTOR and GCN2/ATF4 pathway analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple defined molecular and physiological phenotypes, brush-border transport directly measured\",\n      \"pmids\": [\"21636576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JAK2 (and gain-of-function V617F-JAK2) stimulates SLC6A19 transport activity by increasing carrier protein abundance at the cell membrane (higher Vmax, unchanged affinity); kinase-dead K882E-JAK2 has no effect; JAK2 stimulates transporter insertion into rather than inhibiting retrieval from the plasma membrane.\",\n      \"method\": \"Two-electrode voltage-clamp in Xenopus oocytes, chemiluminescence surface protein quantification, brefeldin A insertion-block experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including kinase-dead control, single lab\",\n      \"pmids\": [\"21964291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"B0AT1 forms functional complexes with the peptidases aminopeptidase N (APN/CD13) and ACE2 in intestinal brush-border membranes; APN increases B0AT1 substrate affinity up to 2.5-fold and increases surface expression; site-directed mutagenesis of APN's catalytic site suggests it increases local substrate concentration to modulate apparent affinity.\",\n      \"method\": \"Co-immunoprecipitation and Blue native electrophoresis of intestinal brush-border membrane proteins; Xenopus oocyte co-expression electrophysiology; site-directed mutagenesis of APN\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal co-IP plus functional reconstitution in oocytes plus mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22677001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PKB/Akt stimulates SLC6A19 transport activity by increasing maximal transport rate (Vmax) without altering substrate affinity; this effect is augmented by PIKfyve in a PKB/Akt phosphorylation-dependent manner; PKB/Akt promotes transporter insertion into the plasma membrane rather than inhibiting retrieval.\",\n      \"method\": \"Two-electrode voltage-clamp in Xenopus oocytes with wild-type and inactive mutant kinases; brefeldin A insertion-block experiments\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead controls and BFA experiments, single lab\",\n      \"pmids\": [\"23234856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Slc6a19 gene expression in intestinal enterocytes is regulated at three levels: CpG dinucleotides in the proximal promoter are highly methylated in crypt cells and fully demethylated in villus cells; histone H3K27Ac (active promoter mark) is present in villus but not crypt cells; transcription factors HNF1a and HNF4a activate transcription in villus enterocytes while SOX9 represses expression in crypts.\",\n      \"method\": \"Fractionation of crypt vs villus enterocytes; bisulfite sequencing for DNA methylation; ChIP for H3K27Ac; gene expression analysis with transcription factor manipulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal epigenetic and transcriptional methods, single lab\",\n      \"pmids\": [\"24121511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nimesulide is a potent inhibitor of B0AT1 (IC50 ~23 μM in proteoliposomes); it shows noncompetitive inhibition with respect to glutamine but competitive inhibition with respect to Na+; molecular docking suggests nimesulide binds an external site on B0AT1, sterically blocking the translocation path.\",\n      \"method\": \"Proteoliposome Na+-[3H]glutamine co-transport assay; inhibition kinetics analysis; molecular docking using B0AT1 homology model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transport inhibition kinetics in reconstituted proteoliposomes plus computational docking, single lab\",\n      \"pmids\": [\"24704252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Collectrin is necessary for both plasma membrane expression and catalytic function of B0AT1 and B0AT3; syntaxin 1A and syntaxin 3 inhibit B0AT1 membrane expression by competing with collectrin; mutagenesis screening identified residues on transmembrane domains 1α, 5, and 7 on one face of B0AT3 as key for collectrin interaction, with distinct residues mediating membrane expression vs. catalytic activation.\",\n      \"method\": \"Monocarboxylate-B0AT1/3 fusion constructs in Xenopus oocytes; mutagenesis screening; electrophysiology and surface expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis plus functional reconstitution identifying specific interaction residues, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"26240152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Each [ACE2:B0AT1] heterodimer constitutes a functional unit for Na+-dependent neutral amino acid transport in situ; radiation inactivation analysis of brush-border membrane vesicles yielded a functional unit molecular weight of 183.7 ± 16.8 kDa, consistent with one ACE2:B0AT1 heterodimer acting as the transport unit within the larger ~345 kDa dimer-of-heterodimers quaternary complex.\",\n      \"method\": \"Radiation inactivation analysis using high-energy electron radiation from a linear accelerator on purified enterocyte brush-border membrane vesicles; target theory molecular weight calculation\",\n      \"journal\": \"Function (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel physical approach in native membranes but single lab, single method\",\n      \"pmids\": [\"34847569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"B0AT1 is expressed in mouse preimplantation embryos along with ACE2; B0AT1 knockout mice show decreased fertility and reduced preimplantation embryo development; B0AT1 mediates the majority of L-proline uptake at the 4-8 cell stage; transport competition experiments confirm B0AT1 substrate specificity in embryos.\",\n      \"method\": \"Slc6a19 knockout mouse; radiolabeled L-proline uptake in oocytes and embryos; competition assays with unlabeled amino acids\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with direct radiolabel transport assay, competition experiments, single lab\",\n      \"pmids\": [\"36611813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nine Hartnup disease-causing B0AT1 variants (R57C, G93R, R95P, R178Q, L242P, G284R, S303L, D517G, P579L) are retained in the endoplasmic reticulum and fail to traffic to the plasma membrane; ER-retained variants R178Q and S303L also significantly disrupt ACE2 intracellular trafficking and its localization to the plasma membrane.\",\n      \"method\": \"Subcellular localization assays (biochemical fractionation and immunofluorescence) of 18 B0AT1 variants; in silico analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic evaluation of 18 variants with biochemical localization assays, identifies ER quality control as mechanism, single lab\",\n      \"pmids\": [\"40852587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC6A19 transports tryptophan into renal cell carcinoma cells, facilitating de novo NAD+ biosynthesis which activates SIRT1; SIRT1 deacetylates histone H3K27, repressing NF-κB p65 transcription and suppressing epithelial-mesenchymal transition; KLF4 inactivation is identified as the key factor for low SLC6A19 expression in RCC cells.\",\n      \"method\": \"Overexpression of SLC6A19 in RCC cells; in vitro and in vivo proliferation/migration/invasion assays; NAD+ measurement; SIRT1 activity assay; H3K27 acetylation ChIP; NF-κB pathway analysis; KLF4 transcription factor binding assays\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway assays in single lab, mechanistic chain established by overexpression with multiple molecular readouts\",\n      \"pmids\": [\"41203631\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC6A19 (B0AT1) is a sodium-dependent, chloride-independent electrogenic transporter that co-transports neutral amino acids with Na+ in a 1:1 stoichiometry at the apical membrane of intestinal enterocytes and renal proximal tubule cells; it requires ancillary proteins (ACE2 in intestine, collectrin/TMEM27 in kidney) for plasma membrane trafficking and full catalytic activity, forms functional digestive complexes with peptidases APN and ACE2 that modulate its substrate affinity and surface expression, and its activity is up-regulated by kinases SGK1-3, PKB/Akt (via PIKfyve), and JAK2 through increased transporter insertion into the plasma membrane; loss-of-function mutations cause Hartnup disorder via ER retention and impaired trafficking, and its absence in mice abolishes epithelial neutral amino acid uptake, impairs mTOR signaling and insulin secretion, and reduces body weight.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC6A19 (B0AT1) is the principal apical, sodium-dependent, chloride-independent transporter that drives bulk reabsorption and absorption of neutral amino acids in renal proximal tubule and intestinal enterocytes, and its loss-of-function mutations cause Hartnup disorder [#0]. It mediates electrogenic Na+:amino acid co-transport with 1:1 stoichiometry through an ordered mechanism in which the amino acid binds before Na+, accepting all neutral amino acids with preference for large non-aromatic substrates [#1, #2]. Catalytically competent surface expression requires tissue-specific ancillary partners — collectrin (TMEM27) in kidney and ACE2 in intestine — with collectrin contacting transmembrane faces that separately govern membrane delivery and catalytic activation [#3, #11]. At the intestinal brush border B0AT1 assembles into functional digestive complexes with the peptidases aminopeptidase N and ACE2, where APN raises apparent substrate affinity and surface expression, and a single ACE2:B0AT1 heterodimer constitutes the minimal transport unit within a larger dimer-of-heterodimers assembly [#7, #12]. Transport activity is acutely up-regulated by kinases SGK1-3, PKB/Akt (via PIKfyve), and JAK2, all increasing transporter abundance at the plasma membrane without changing affinity [#4, #6, #8]. Genetic ablation in mice abolishes epithelial neutral amino acid uptake and reduces body weight, postprandial insulin secretion, and intestinal mTOR signaling while activating the GCN2/ATF4 stress response, establishing the transporter as essential for systemic nutrient sensing [#5]. Hartnup-causing variants act through endoplasmic reticulum retention and failure to reach the plasma membrane, with some variants additionally disrupting ACE2 trafficking [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the molecular identity of the long-sought intestinal/renal neutral amino acid transporter and tied it directly to a human Mendelian disease.\",\n      \"evidence\": \"Positional cloning, mutation identification, and in vitro transport assays in heterologous systems\",\n      \"pmids\": [\"15286787\", \"15286788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transport mechanism and stoichiometry not yet resolved\", \"Ancillary requirements for surface expression unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the biophysical transport mechanism, answering how ion coupling and substrate order produce electrogenic uptake.\",\n      \"evidence\": \"Two-electrode voltage-clamp with simultaneous charge and radiolabeled amino acid flux in Xenopus oocytes; kinetic modeling\",\n      \"pmids\": [\"15804236\", \"16133263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discrepancy between random-order and ordered binding models across the two studies\", \"Structural basis of the translocation cycle not determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified tissue-specific ancillary proteins required for surface delivery, explaining why the transporter functions differently in kidney versus intestine.\",\n      \"evidence\": \"Heterologous co-expression of collectrin/TMEM27 and ACE2 in oocytes and cell lines (review synthesis)\",\n      \"pmids\": [\"19472175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular interaction interface not mapped\", \"Review-level synthesis rather than single primary dataset\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed acute kinase regulation by SGK isoforms acts by stabilizing transporter at the membrane rather than altering catalysis.\",\n      \"evidence\": \"Voltage-clamp, surface protein quantification, and brefeldin A insertion-block in oocytes\",\n      \"pmids\": [\"20511718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation site on SLC6A19 not identified\", \"Physiological context of SGK regulation untested in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"JAK2 was added as a regulator acting through increased transporter insertion, with a kinase-dead control establishing catalytic dependence.\",\n      \"evidence\": \"Voltage-clamp, chemiluminescence surface quantification, BFA block, K882E kinase-dead mutant in oocytes\",\n      \"pmids\": [\"21964291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate phosphorylation not shown\", \"Relevance to JAK2-V617F disease states unexplored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the systemic physiological consequence of losing the transporter, linking epithelial amino acid uptake to body weight, insulin secretion, and nutrient signaling.\",\n      \"evidence\": \"Slc6a19 knockout mouse with brush-border vesicle transport assays, insulin measurements, and mTOR/GCN2-ATF4 pathway analysis\",\n      \"pmids\": [\"21636576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions to phenotype not dissected\", \"Mechanism connecting transport loss to mTOR not resolved at molecular level\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed that the transporter operates within a brush-border digestive complex where peptidases shape its kinetic behavior.\",\n      \"evidence\": \"Reciprocal co-IP and blue-native electrophoresis of brush-border membranes, oocyte co-expression, APN catalytic-site mutagenesis\",\n      \"pmids\": [\"22677001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the multi-protein complex not defined here\", \"In vivo physiological role of APN coupling untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended kinase regulation to PKB/Akt acting cooperatively with PIKfyve to promote membrane insertion.\",\n      \"evidence\": \"Voltage-clamp with wild-type and inactive kinase mutants plus BFA block in oocytes\",\n      \"pmids\": [\"23234856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation target unidentified\", \"Single lab, oocyte-only system\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined how spatial expression along the crypt-villus axis is set, integrating DNA methylation, histone marks, and transcription factors.\",\n      \"evidence\": \"Crypt/villus fractionation, bisulfite sequencing, H3K27Ac ChIP, and HNF1a/HNF4a/SOX9 manipulation\",\n      \"pmids\": [\"24121511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals controlling these epigenetic states unknown\", \"Conservation of regulation in human tissue untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided a pharmacological tool and inhibitor binding model, supporting an external blocking site on the translocation path.\",\n      \"evidence\": \"Proteoliposome Na+-glutamine co-transport inhibition kinetics and molecular docking with a homology model\",\n      \"pmids\": [\"24704252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitor binding site not experimentally validated\", \"Docking based on homology model lacking experimental structure\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped specific collectrin-interacting residues and showed membrane delivery and catalytic activation are separable functions.\",\n      \"evidence\": \"Fusion constructs, mutagenesis screening, electrophysiology, and surface expression in oocytes; syntaxin competition\",\n      \"pmids\": [\"26240152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the collectrin contact face not solved\", \"Syntaxin regulation in native epithelium untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Determined the functional transport unit in native membranes, showing one ACE2:B0AT1 heterodimer suffices within the larger assembly.\",\n      \"evidence\": \"Radiation inactivation analysis of enterocyte brush-border membrane vesicles with target-theory mass calculation\",\n      \"pmids\": [\"34847569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method and single lab\", \"Role of the higher-order dimer-of-heterodimers in function unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the transporter's role beyond epithelia, showing it supplies proline to early embryos and supports fertility.\",\n      \"evidence\": \"Slc6a19 knockout mouse with radiolabeled L-proline uptake and amino acid competition assays in embryos\",\n      \"pmids\": [\"36611813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking proline uptake to embryo development not defined\", \"Human relevance of embryonic expression untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified the molecular pathology of Hartnup variants as ER retention, and showed some variants impair ACE2 trafficking.\",\n      \"evidence\": \"Subcellular localization assays and in silico analysis of 18 disease variants\",\n      \"pmids\": [\"40852587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER retention is rescuable not addressed\", \"Functional consequence of ACE2 mistrafficking not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated the transporter in cancer biology via tryptophan-fueled NAD+/SIRT1 signaling that suppresses EMT in renal carcinoma.\",\n      \"evidence\": \"SLC6A19 overexpression in RCC cells with NAD+ measurement, SIRT1 activity, H3K27ac ChIP, NF-kB and KLF4 analyses\",\n      \"pmids\": [\"41203631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain rests on overexpression rather than endogenous modulation\", \"Generalizability beyond RCC unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"An experimentally determined high-resolution structure of the transport cycle and a unifying model reconciling ordered versus random substrate binding remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure of the human transporter in the corpus\", \"Direct phosphorylation sites underlying kinase regulation unidentified\", \"In vivo significance of kinase regulation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 5, 13]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 6, 8, 11, 12]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-8963743\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 14]}\n    ],\n    \"complexes\": [\n      \"ACE2:B0AT1 heterodimer (dimer-of-heterodimers)\",\n      \"B0AT1-APN-ACE2 brush-border digestive complex\",\n      \"collectrin (TMEM27):B0AT1 complex\"\n    ],\n    \"partners\": [\n      \"ACE2\",\n      \"TMEM27\",\n      \"APN\",\n      \"SGK1\",\n      \"JAK2\",\n      \"AKT1\",\n      \"STX1A\",\n      \"STX3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}