{"gene":"SLC13A2","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1996,"finding":"NaDC-1 expressed in COS-7 cells mediates sodium-dependent transport of succinate and citrate; transport kinetics show a Hill coefficient of ~2.9 for sodium activation, indicating three Na+ ions are co-transported per succinate; citrate transport is stimulated by acidic pH while succinate transport is pH-insensitive; lithium inhibits succinate transport.","method":"Heterologous expression in COS-7 mammalian cells, radiolabeled uptake assays, kinetic analysis","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional reconstitution in heterologous system with kinetic characterization, single lab but multiple orthogonal substrate/ion conditions tested","pmids":["8596711"],"is_preprint":false},{"year":1998,"finding":"His-106 in NaDC-1 is required for normal cell-surface membrane expression rather than for catalytic function; mutagenesis of His-153 and His-569 confers insensitivity to DEPC inhibition, implicating these residues in DEPC binding but not transport activity; no other histidine residue is individually essential for transport.","method":"Site-directed mutagenesis of all 11 histidine residues, expression in Xenopus oocytes, radiolabeled succinate uptake, cell-surface biotinylation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis of all 11 residues with surface biotinylation and transport kinetics in a single rigorous study","pmids":["9512488"],"is_preprint":false},{"year":1999,"finding":"Asp-373 (TM8) substitutions alter sodium affinity and cation selectivity, implicating its carbonyl oxygen in cation-binding site topology; Glu-475 (TM9) substitutions dramatically reduce transport and alter substrate/sodium affinity; E475A produces voltage-dependent substrate-induced currents with current reversal at −30 mV, suggesting a role in cation binding and possible anion channel activity; mutations at both Asp-373 and Glu-475 also affect succinate Km, indicating these residues contribute to the substrate-binding site.","method":"Site-directed mutagenesis of acidic residues, two-electrode voltage clamp and radiolabeled uptake in Xenopus oocytes, kinetic analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus electrophysiology with kinetic characterization in a single thorough study","pmids":["10360950"],"is_preprint":false},{"year":1999,"finding":"None of the 11 individual cysteine residues are essential for NaDC-1 transport activity, but impermeant cysteine reagent pCMBS inhibits transport; Cys-227 (TM5) and Cys-476 (TM9) are the pCMBS-accessible residues; cumulative cysteine mutagenesis progressively reduces transport activity and expression, indicating multiple cysteines collectively support protein stability or trafficking to the plasma membrane.","method":"Site-directed mutagenesis of all 11 cysteine residues, pCMBS inhibition assays, expression in Xenopus oocytes, radiolabeled uptake","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — complete systematic mutagenesis of all 11 residues with chemical accessibility probing in a single rigorous study","pmids":["10548552"],"is_preprint":false},{"year":1999,"finding":"Protein kinase C (PKC) activation by PMA or DAG inhibits NaDC-1 succinate transport by up to 95% in Xenopus oocytes; inhibition is dose-dependent and prevented by staurosporine; consensus PKC phosphorylation sites on NaDC-1 are not required for this inhibition; PMA causes ~30% reduction in plasma membrane NaDC-1 protein; cytochalasin D (microfilament disruptor/endocytosis inhibitor) partially prevents PMA inhibition, indicating the mechanism involves endocytosis plus direct activity inhibition. PKA activation has no effect.","method":"PKC/PKA pharmacological activation in Xenopus oocytes expressing NaDC-1, site-directed mutagenesis of consensus phosphorylation sites, surface protein quantification, cytochalasin D treatment","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pharmacological, mutagenesis, and surface quantification methods combined in a single study","pmids":["10446305"],"is_preprint":false},{"year":2000,"finding":"Lys-84 (cytoplasmic end of TM3) mutation to Ala increases the Km for succinate ~6-fold (from 0.3 mM to 1.8 mM) without affecting surface expression, implicating Lys-84 in substrate binding. Arg-349 (extracellular end of TM7) mutation alters succinate handling (inhibition at high succinate concentrations) with normal sodium and citrate kinetics; both residues affect succinate handling but are not essential for surface targeting.","method":"Site-directed mutagenesis, expression in Xenopus oocytes, radiolabeled uptake, transport kinetics","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with kinetic readout, single lab, single study","pmids":["10970779"],"is_preprint":false},{"year":2000,"finding":"Chronic metabolic acidosis increases NaDC-1 mRNA abundance (detectable at 3 hours, correlating with acidosis severity) and apical membrane NaDC-1 protein abundance (maximal in S2 segment, time-dependent) in rat kidney proximal tubule; alkali feeding has no effect on NaDC-1 mRNA or protein. NaDC-1 localizes to the apical membrane of the proximal tubule.","method":"Rat metabolic acidosis model, immunohistochemistry, immunoblot of brush border membrane vesicles, mRNA quantification","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with protein and mRNA quantification and immunolocalization, single lab","pmids":["10886565"],"is_preprint":false},{"year":2004,"finding":"In OKP cells (proximal tubule model), media acidification increases Na-dependent citrate uptake post-transcriptionally (NaDC-1 mRNA abundance is unchanged); the opossum NaDC-1 ortholog shows ≥3 Na:1 citrate stoichiometry, dicarboxylate/tricarboxylate selectivity, pH-dependent citrate transport, and pH-independent succinate transport when expressed in Xenopus oocytes.","method":"cDNA cloning, Xenopus oocyte expression, radiolabeled citrate uptake, GFP-tagged construct transfection in OKP cells, mRNA quantification under pH variation","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in oocytes plus cell-based transport assay with pH manipulation, single lab","pmids":["14973148"],"is_preprint":false},{"year":2010,"finding":"Acid-induced stimulation of NaDC-1 activity requires a functional endothelin B (ETB) receptor: pharmacological ETB blockade (BQ788) abolishes acid and ET-1 stimulation of NaDC-1 in OKP cells; ETB knockout mice show no increase in brush border NaDC-1 activity upon acid feeding. Using ETА/ETB chimeric constructs, ET-1 stimulation of NaDC-1 requires the receptor C-terminal tail (from either ETA or ETB) and is greatest with the ETB transmembrane domain plus a C-terminal tail.","method":"Pharmacological ETB antagonism in OKP cells, ETB knockout mouse model, brush border membrane vesicle NaDC-1 activity assay, ETА/ETB chimeric receptor constructs","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in vivo plus pharmacological and chimeric receptor approaches in vitro, replicated across model systems","pmids":["20703215"],"is_preprint":false},{"year":2013,"finding":"SLC26A6 physically and functionally interacts with NaDC-1: the STAS domain of SLC26A6 and the first intracellular loop of NaDC-1 mediate their physical interaction (biochemical pull-down/co-expression) and functional cross-regulation. NaDC-1 enhances SLC26A6 transport activity, while SLC26A6 inhibits NaDC-1 transport activity in an activity-dependent manner. Slc26a6-null mice show increased renal/intestinal sodium-dependent succinate uptake and hypocitraturia, consistent with loss of SLC26A6-mediated NaDC-1 inhibition.","method":"Co-expression in Xenopus oocytes, Slc26a6-knockout mouse model, biochemical domain interaction analysis (STAS domain and NaDC-1 intracellular loop), transport assays","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional regulation shown in oocytes, physical interaction domain-mapped, validated in knockout mouse model","pmids":["23833257"],"is_preprint":false},{"year":2016,"finding":"In normal human kidney, NaDC-1 (SLC13A2) protein localizes exclusively to the apical (luminal) membrane throughout the entire proximal tubule (including proximal convoluted and proximal straight tubule), co-localizing with NBCe1; NaDC-1 is not detectable in other renal cell types or in renal tumors (clear cell RCC, papillary RCC, oncocytoma, chromophobe carcinoma).","method":"Immunoblot (~61 kDa band), immunohistochemistry, colocalization with NBCe1 in human kidney tissue sections","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization in human tissue with colocalization marker, single lab","pmids":["27927654"],"is_preprint":false},{"year":2018,"finding":"Acid stimulation of NaDC-1 activity requires Pyk2/c-Src and a Raf1-ERK1/2-p90RSK signaling cascade; these pathways are distinct from and not downstream of ET-1/ETB signaling. Pyk2-null mice fail to show NH4Cl-induced increase in brush border NaDC-1 activity; ERK1/2 phosphorylation by acid is Pyk2-independent; Raf1 and p90RSK inhibition blocks acid but not ET-1 stimulation of NaDC-1.","method":"Pyk2 and c-Src inhibition in OKP cells, Pyk2-knockout mice, NH4Cl loading, brush border vesicle NaDC-1 activity assay, immunoblot for pathway phosphorylation, [14C]-citrate uptake","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse plus pharmacological pathway dissection in two model systems with multiple orthogonal readouts","pmids":["29678998"],"is_preprint":false},{"year":2025,"finding":"SLC13A2 promotes liver regeneration by importing citrate into hepatocytes, which serves as substrate for ACLY-dependent acetyl-CoA generation and de novo cholesterol biosynthesis via increased SREBP2 cleavage and upregulation of LDLR and HMGCR; ACLY inhibition or HMGCR inhibition (lovastatin) abrogates SLC13A2-mediated regeneration. Liver-specific overexpression promotes, and liver-specific depletion attenuates, liver regeneration after partial hepatectomy in mice.","method":"Partial hepatectomy mouse model, liver-specific SLC13A2 overexpression/knockout (AAV), metabolic flux analysis, ACLY inhibitor, lovastatin treatment, SREBP2 cleavage assay, cholesterol synthesis measurement","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain-and-loss-of-function in vivo, metabolic flux analysis, and pathway inhibitor rescue in a single study with multiple orthogonal methods","pmids":["39824985"],"is_preprint":false},{"year":2026,"finding":"In hepatocellular carcinoma, SLC13A2-imported citrate generates acetyl-CoA that acetylates pyruvate kinase M2 (PKM2), triggering its degradation; reduced PKM2 activity limits pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. SLC13A2-imported citrate also increases intracellular protein acetylation (including histone acetylation), altering transcriptional regulation and contributing to tumor suppression. AAV-mediated liver-specific SLC13A2 knockout promotes, while overexpression ameliorates, HCC progression.","method":"AAV-mediated liver-specific knockout/overexpression in mouse HCC models, metabolic flux analysis, PKM2 acetylation and degradation assays, histone acetylation analysis, acetyl-CoA measurement","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with mechanistic biochemical assays in a single study, not yet independently replicated","pmids":["41950310"],"is_preprint":false}],"current_model":"SLC13A2 (NaDC-1) is an apical membrane Na+/dicarboxylate cotransporter in renal proximal tubule that mediates electrogenic, sodium-coupled uptake of TCA cycle intermediates (citrate, succinate) with ≥3 Na+ per substrate; its activity is acutely downregulated via PKC-driven endocytosis, and chronically upregulated in metabolic acidosis through a signaling cascade requiring ETB receptor activation upstream of Pyk2/c-Src and Raf1-ERK1/2-p90RSK; SLC26A6 physically interacts with NaDC-1's first intracellular loop via its STAS domain to inhibit NaDC-1 activity, providing feedback regulation of oxalate/citrate homeostasis; beyond the kidney, SLC13A2-imported citrate fuels ACLY-dependent acetyl-CoA production for de novo cholesterol synthesis and protein/histone acetylation, with demonstrated roles in liver regeneration and tumor suppression in hepatocellular carcinoma."},"narrative":{"mechanistic_narrative":"SLC13A2 (NaDC-1) is an apical-membrane, sodium-coupled cotransporter of the renal proximal tubule that mediates electrogenic uptake of TCA-cycle dicarboxylates and tricarboxylates, providing a physiological route for citrate and succinate reabsorption [PMID:8596711, PMID:10886565, PMID:27927654]. Transport is electrogenic and high-stoichiometry, with a Hill coefficient of ~2.9 for sodium indicating three Na+ co-transported per succinate, and shows pH-dependent citrate handling versus pH-insensitive succinate handling [PMID:8596711, PMID:14973148]. Systematic mutagenesis localized cation- and substrate-binding determinants to acidic residues Asp-373 (TM8) and Glu-475 (TM9) and to Lys-84 and Arg-349, while His-106 and multiple cysteines are required not for catalysis but for surface expression and trafficking [PMID:9512488, PMID:10360950, PMID:10548552, PMID:10970779]. Activity is acutely suppressed by PKC activation through endocytic removal and direct inhibition independent of consensus phosphorylation sites [PMID:10446305], and is chronically upregulated in metabolic acidosis via increased apical protein abundance through two parallel signaling arms: an endothelin-1/ETB-receptor pathway and a Pyk2/c-Src – Raf1-ERK1/2-p90RSK cascade [PMID:10886565, PMID:20703215, PMID:29678998]. SLC13A2 is reciprocally regulated by SLC26A6, whose STAS domain binds the first intracellular loop of NaDC-1 to inhibit its transport and thereby couple citrate and oxalate handling [PMID:23833257]. Beyond the kidney, SLC13A2-imported citrate fuels ACLY-dependent acetyl-CoA production for de novo cholesterol synthesis, driving hepatocyte proliferation during liver regeneration [PMID:39824985], and supports protein and histone acetylation that promotes PKM2 acetylation/degradation and tumor suppression in hepatocellular carcinoma [PMID:41950310].","teleology":[{"year":1996,"claim":"Established NaDC-1 as a sodium-coupled di/tricarboxylate cotransporter and defined its core transport mechanism, answering what substrates and ion stoichiometry the protein uses.","evidence":"Heterologous expression in COS-7 cells with radiolabeled succinate/citrate uptake and Hill-coefficient kinetic analysis","pmids":["8596711"],"confidence":"High","gaps":["No structural model of the transport cycle","pH-sensitivity mechanism for citrate versus succinate not defined at the residue level"]},{"year":1998,"claim":"Distinguished residues needed for catalysis from those needed for surface delivery, showing His-106 governs trafficking rather than transport.","evidence":"Systematic mutagenesis of all 11 histidines with cell-surface biotinylation and succinate uptake in Xenopus oocytes","pmids":["9512488"],"confidence":"High","gaps":["Trafficking machinery interacting with His-106 not identified"]},{"year":1999,"claim":"Mapped cation- and substrate-binding determinants to acidic transmembrane residues, building a topological picture of the binding site.","evidence":"Site-directed mutagenesis of acidic residues with two-electrode voltage clamp and uptake kinetics in oocytes","pmids":["10360950"],"confidence":"High","gaps":["No high-resolution structure to confirm residue geometry","Reported anion-channel-like behavior of E475A not mechanistically resolved"]},{"year":1999,"claim":"Showed cysteines are collectively required for stability/trafficking rather than individually for transport, and identified pCMBS-accessible residues marking the aqueous transport pathway.","evidence":"Complete cysteine mutagenesis with pCMBS accessibility probing in oocytes","pmids":["10548552"],"confidence":"High","gaps":["Conformational states sampled by accessible cysteines not defined"]},{"year":1999,"claim":"Defined PKC as an acute negative regulator acting through endocytosis plus direct inhibition, independent of canonical phosphorylation sites.","evidence":"PKC/PKA pharmacology, phosphosite mutagenesis, surface protein quantification and cytochalasin D treatment in oocytes","pmids":["10446305"],"confidence":"High","gaps":["Molecular target of PKC if not direct phosphorylation of NaDC-1 unknown","Endocytic adaptors not identified"]},{"year":2000,"claim":"Identified additional substrate-handling residues (Lys-84, Arg-349) refining the succinate-binding site.","evidence":"Site-directed mutagenesis with transport kinetics in oocytes","pmids":["10970779"],"confidence":"Medium","gaps":["Single-lab kinetic inference without structural confirmation","Distinct effects on succinate versus citrate not mechanistically explained"]},{"year":2000,"claim":"Demonstrated physiological regulation in vivo, showing metabolic acidosis raises apical NaDC-1 mRNA and protein in proximal tubule while alkali has no effect.","evidence":"Rat acidosis model with immunohistochemistry, brush-border immunoblot and mRNA quantification","pmids":["10886565"],"confidence":"Medium","gaps":["Signaling pathway linking acidosis to expression not yet defined","Segment-specific regulation mechanism unclear"]},{"year":2004,"claim":"Showed acid stimulation can occur post-transcriptionally, indicating regulation acts on protein activity/trafficking and not only transcription.","evidence":"OKP cell acidification with Na-dependent citrate uptake, GFP-tagged constructs, and oocyte characterization of the opossum ortholog","pmids":["14973148"],"confidence":"Medium","gaps":["Post-transcriptional mechanism (stability vs trafficking) not resolved","Reconciliation with transcriptional induction in vivo incomplete"]},{"year":2010,"claim":"Identified the ETB receptor as a required upstream node for acid stimulation, defining a receptor-level entry point to the regulatory cascade.","evidence":"ETB antagonism and ETA/ETB chimeras in OKP cells plus ETB-knockout mice with brush-border activity assays","pmids":["20703215"],"confidence":"High","gaps":["Downstream effectors linking ETB to transporter at this stage unknown","Source of acid-induced ET-1 not defined"]},{"year":2013,"claim":"Defined SLC26A6 as a direct physical and reciprocal functional regulator, coupling citrate and oxalate handling at the membrane.","evidence":"STAS-domain/intracellular-loop interaction mapping, oocyte co-expression, and Slc26a6-null mice with succinate uptake and citraturia readouts","pmids":["23833257"],"confidence":"High","gaps":["Structural basis of STAS-loop binding not resolved","Whether interaction is constitutive or regulated is unclear"]},{"year":2018,"claim":"Resolved the intracellular signaling cascade for acid stimulation as a Pyk2/c-Src and Raf1-ERK1/2-p90RSK pathway distinct from ETB signaling.","evidence":"Pyk2/c-Src inhibition in OKP cells, Pyk2-knockout mice, NH4Cl loading and brush-border activity assays with pathway phospho-immunoblots","pmids":["29678998"],"confidence":"High","gaps":["How parallel ETB and Pyk2 arms converge on the transporter unknown","Terminal step modifying NaDC-1 trafficking not identified"]},{"year":2025,"claim":"Extended SLC13A2 function beyond the kidney, showing citrate import feeds ACLY-dependent acetyl-CoA and cholesterol synthesis to drive liver regeneration.","evidence":"Partial hepatectomy with liver-specific AAV overexpression/knockout, metabolic flux analysis, and ACLY/HMGCR inhibitor rescue in mice","pmids":["39824985"],"confidence":"High","gaps":["Whether the same citrate-acetyl-CoA axis operates in renal cells untested","Regulation of hepatic SLC13A2 expression not defined"]},{"year":2026,"claim":"Connected SLC13A2 citrate import to acetylation-driven PKM2 degradation and histone acetylation, establishing a tumor-suppressive role in hepatocellular carcinoma.","evidence":"Liver-specific AAV knockout/overexpression in mouse HCC models with metabolic flux, PKM2 acetylation/degradation and histone acetylation assays","pmids":["41950310"],"confidence":"Medium","gaps":["Not independently replicated","Acetyltransferase mediating PKM2 acetylation not identified","Relevance to human HCC outcomes untested"]},{"year":null,"claim":"How the parallel acidosis-sensing pathways (ETB and Pyk2/Raf-ERK-RSK) ultimately converge to modify NaDC-1 protein trafficking, and whether the hepatic citrate-acetyl-CoA functions generalize to kidney, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified terminal modification or adaptor that increases apical NaDC-1 abundance","No structural model linking residue-level binding data to the transport cycle","Cross-tissue unification of transport and metabolic roles incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,10]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,13]}],"complexes":[],"partners":["SLC26A6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13183","full_name":"Solute carrier family 13 member 2","aliases":["Na(+)/dicarboxylate cotransporter 1","NaDC-1","Renal sodium/dicarboxylate cotransporter"],"length_aa":592,"mass_kda":64.4,"function":"Low-affinity sodium-dicarboxylate cotransporter, that mediates the entry of citric acid cycle intermediates, such as succinate, citrate, fumarate and alpha-ketoglutarate (2-oxoglutarate) into the small intestine and renal proximal tubule (PubMed:10894787, PubMed:8967342, PubMed:9668069). Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic (PubMed:10894787, PubMed:8967342, PubMed:9668069). Citrate is transported in protonated form as a divalent anion, rather than the trivalent form which is normally found in blood (PubMed:10894787). Has a critical role in renal dicarboxylate transport (By similarity)","subcellular_location":"Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13183/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC13A2","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC13A2","total_profiled":1310},"omim":[{"mim_id":"608305","title":"SOLUTE CARRIER FAMILY 13 (SODIUM-DEPENDENT CITRATE TRANSPORTER), MEMBER 5; SLC13A5","url":"https://www.omim.org/entry/608305"},{"mim_id":"606411","title":"SOLUTE CARRIER FAMILY 13 (SODIUM-DEPENDENT DICARBOXYLATE TRANSPORTER), MEMBER 3; SLC13A3","url":"https://www.omim.org/entry/606411"},{"mim_id":"604148","title":"SOLUTE CARRIER FAMILY 13 (SODIUM-DEPENDENT DICARBOXYLATE TRANSPORTER), MEMBER 2; SLC13A2","url":"https://www.omim.org/entry/604148"},{"mim_id":"603088","title":"SOLUTE CARRIER FAMILY 31 (COPPER TRANSPORTER), MEMBER 2; SLC31A2","url":"https://www.omim.org/entry/603088"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":121.8},{"tissue":"kidney","ntpm":40.2},{"tissue":"salivary gland","ntpm":45.4}],"url":"https://www.proteinatlas.org/search/SLC13A2"},"hgnc":{"alias_symbol":["NaDC-1"],"prev_symbol":[]},"alphafold":{"accession":"Q13183","domains":[{"cath_id":"-","chopping":"32-167_210-393_406-573","consensus_level":"medium","plddt":89.0857,"start":32,"end":573}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13183","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13183-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13183-F1-predicted_aligned_error_v6.png","plddt_mean":83.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC13A2","jax_strain_url":"https://www.jax.org/strain/search?query=SLC13A2"},"sequence":{"accession":"Q13183","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13183.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13183/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13183"}},"corpus_meta":[{"pmid":"10886565","id":"PMC_10886565","title":"Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney.","date":"2000","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/10886565","citation_count":90,"is_preprint":false},{"pmid":"23833257","id":"PMC_23833257","title":"SLC26A6 and NaDC-1 transporters interact to regulate oxalate and citrate homeostasis.","date":"2013","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/23833257","citation_count":60,"is_preprint":false},{"pmid":"9512488","id":"PMC_9512488","title":"Mutational analysis of histidine residues in the rabbit Na+/dicarboxylate co-transporter NaDC-1.","date":"1998","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9512488","citation_count":34,"is_preprint":false},{"pmid":"10548552","id":"PMC_10548552","title":"Cysteine residues in the Na+/dicarboxylate co-transporter, NaDC-1.","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10548552","citation_count":29,"is_preprint":false},{"pmid":"10446305","id":"PMC_10446305","title":"Protein kinase C-mediated regulation of the renal Na(+)/dicarboxylate cotransporter, NaDC-1.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10446305","citation_count":28,"is_preprint":false},{"pmid":"10360950","id":"PMC_10360950","title":"Acidic residues involved in cation and substrate interactions in the Na+/dicarboxylate cotransporter, NaDC-1.","date":"1999","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10360950","citation_count":26,"is_preprint":false},{"pmid":"20703215","id":"PMC_20703215","title":"Acid regulation of NaDC-1 requires a functional endothelin B receptor.","date":"2010","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/20703215","citation_count":21,"is_preprint":false},{"pmid":"27927654","id":"PMC_27927654","title":"Expression of sodium-dependent dicarboxylate transporter 1 (NaDC1/SLC13A2) in normal and neoplastic human kidney.","date":"2016","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27927654","citation_count":18,"is_preprint":false},{"pmid":"29678998","id":"PMC_29678998","title":"Acid Stimulation of the Citrate Transporter NaDC-1 Requires Pyk2 and ERK1/2 Signaling Pathways.","date":"2018","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/29678998","citation_count":17,"is_preprint":false},{"pmid":"14973148","id":"PMC_14973148","title":"OKP cells express the Na-dicarboxylate cotransporter NaDC-1.","date":"2004","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14973148","citation_count":16,"is_preprint":false},{"pmid":"10970779","id":"PMC_10970779","title":"Role of cationic amino acids in the Na+/dicarboxylate co-transporter NaDC-1.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10970779","citation_count":14,"is_preprint":false},{"pmid":"8596711","id":"PMC_8596711","title":"Expression of the renal Na+/dicarboxylate cotransporter, NaDC-1, in COS-7 cells.","date":"1996","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8596711","citation_count":12,"is_preprint":false},{"pmid":"27639591","id":"PMC_27639591","title":"Evidence for epistatic interaction between VDR and SLC13A2 genes in the pathogenesis of hypocitraturia in recurrent calcium oxalate stone formers.","date":"2016","source":"Journal of nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/27639591","citation_count":12,"is_preprint":false},{"pmid":"39824985","id":"PMC_39824985","title":"SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis.","date":"2025","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39824985","citation_count":6,"is_preprint":false},{"pmid":"34458928","id":"PMC_34458928","title":"SLC26A6 and NADC‑1: Future direction of nephrolithiasis and calculus‑related hypertension research (Review).","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34458928","citation_count":5,"is_preprint":false},{"pmid":"30155711","id":"PMC_30155711","title":"rs11567842 SNP in SLC13A2 gene associates with hypocitraturia in Thai patients with nephrolithiasis.","date":"2018","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/30155711","citation_count":5,"is_preprint":false},{"pmid":"41950310","id":"PMC_41950310","title":"SLC13A2-transported citrate remodels transcriptional regulation through protein acetylation to suppress tumor growth.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/41950310","citation_count":0,"is_preprint":false},{"pmid":"40868238","id":"PMC_40868238","title":"Investigation of rs11568476 Polymorphism in the SLC13A2 Gene in Turkish Patients with Hypocitraturia and Calcium-Containing Kidney Stones.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40868238","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11146,"output_tokens":4152,"usd":0.047859,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12037,"output_tokens":3913,"usd":0.079005,"stage2_stop_reason":"end_turn"},"total_usd":0.126864,"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\": 1996,\n      \"finding\": \"NaDC-1 expressed in COS-7 cells mediates sodium-dependent transport of succinate and citrate; transport kinetics show a Hill coefficient of ~2.9 for sodium activation, indicating three Na+ ions are co-transported per succinate; citrate transport is stimulated by acidic pH while succinate transport is pH-insensitive; lithium inhibits succinate transport.\",\n      \"method\": \"Heterologous expression in COS-7 mammalian cells, radiolabeled uptake assays, kinetic analysis\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution in heterologous system with kinetic characterization, single lab but multiple orthogonal substrate/ion conditions tested\",\n      \"pmids\": [\"8596711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"His-106 in NaDC-1 is required for normal cell-surface membrane expression rather than for catalytic function; mutagenesis of His-153 and His-569 confers insensitivity to DEPC inhibition, implicating these residues in DEPC binding but not transport activity; no other histidine residue is individually essential for transport.\",\n      \"method\": \"Site-directed mutagenesis of all 11 histidine residues, expression in Xenopus oocytes, radiolabeled succinate uptake, cell-surface biotinylation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis of all 11 residues with surface biotinylation and transport kinetics in a single rigorous study\",\n      \"pmids\": [\"9512488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Asp-373 (TM8) substitutions alter sodium affinity and cation selectivity, implicating its carbonyl oxygen in cation-binding site topology; Glu-475 (TM9) substitutions dramatically reduce transport and alter substrate/sodium affinity; E475A produces voltage-dependent substrate-induced currents with current reversal at −30 mV, suggesting a role in cation binding and possible anion channel activity; mutations at both Asp-373 and Glu-475 also affect succinate Km, indicating these residues contribute to the substrate-binding site.\",\n      \"method\": \"Site-directed mutagenesis of acidic residues, two-electrode voltage clamp and radiolabeled uptake in Xenopus oocytes, kinetic analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus electrophysiology with kinetic characterization in a single thorough study\",\n      \"pmids\": [\"10360950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"None of the 11 individual cysteine residues are essential for NaDC-1 transport activity, but impermeant cysteine reagent pCMBS inhibits transport; Cys-227 (TM5) and Cys-476 (TM9) are the pCMBS-accessible residues; cumulative cysteine mutagenesis progressively reduces transport activity and expression, indicating multiple cysteines collectively support protein stability or trafficking to the plasma membrane.\",\n      \"method\": \"Site-directed mutagenesis of all 11 cysteine residues, pCMBS inhibition assays, expression in Xenopus oocytes, radiolabeled uptake\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — complete systematic mutagenesis of all 11 residues with chemical accessibility probing in a single rigorous study\",\n      \"pmids\": [\"10548552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Protein kinase C (PKC) activation by PMA or DAG inhibits NaDC-1 succinate transport by up to 95% in Xenopus oocytes; inhibition is dose-dependent and prevented by staurosporine; consensus PKC phosphorylation sites on NaDC-1 are not required for this inhibition; PMA causes ~30% reduction in plasma membrane NaDC-1 protein; cytochalasin D (microfilament disruptor/endocytosis inhibitor) partially prevents PMA inhibition, indicating the mechanism involves endocytosis plus direct activity inhibition. PKA activation has no effect.\",\n      \"method\": \"PKC/PKA pharmacological activation in Xenopus oocytes expressing NaDC-1, site-directed mutagenesis of consensus phosphorylation sites, surface protein quantification, cytochalasin D treatment\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological, mutagenesis, and surface quantification methods combined in a single study\",\n      \"pmids\": [\"10446305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Lys-84 (cytoplasmic end of TM3) mutation to Ala increases the Km for succinate ~6-fold (from 0.3 mM to 1.8 mM) without affecting surface expression, implicating Lys-84 in substrate binding. Arg-349 (extracellular end of TM7) mutation alters succinate handling (inhibition at high succinate concentrations) with normal sodium and citrate kinetics; both residues affect succinate handling but are not essential for surface targeting.\",\n      \"method\": \"Site-directed mutagenesis, expression in Xenopus oocytes, radiolabeled uptake, transport kinetics\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with kinetic readout, single lab, single study\",\n      \"pmids\": [\"10970779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Chronic metabolic acidosis increases NaDC-1 mRNA abundance (detectable at 3 hours, correlating with acidosis severity) and apical membrane NaDC-1 protein abundance (maximal in S2 segment, time-dependent) in rat kidney proximal tubule; alkali feeding has no effect on NaDC-1 mRNA or protein. NaDC-1 localizes to the apical membrane of the proximal tubule.\",\n      \"method\": \"Rat metabolic acidosis model, immunohistochemistry, immunoblot of brush border membrane vesicles, mRNA quantification\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with protein and mRNA quantification and immunolocalization, single lab\",\n      \"pmids\": [\"10886565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In OKP cells (proximal tubule model), media acidification increases Na-dependent citrate uptake post-transcriptionally (NaDC-1 mRNA abundance is unchanged); the opossum NaDC-1 ortholog shows ≥3 Na:1 citrate stoichiometry, dicarboxylate/tricarboxylate selectivity, pH-dependent citrate transport, and pH-independent succinate transport when expressed in Xenopus oocytes.\",\n      \"method\": \"cDNA cloning, Xenopus oocyte expression, radiolabeled citrate uptake, GFP-tagged construct transfection in OKP cells, mRNA quantification under pH variation\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in oocytes plus cell-based transport assay with pH manipulation, single lab\",\n      \"pmids\": [\"14973148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Acid-induced stimulation of NaDC-1 activity requires a functional endothelin B (ETB) receptor: pharmacological ETB blockade (BQ788) abolishes acid and ET-1 stimulation of NaDC-1 in OKP cells; ETB knockout mice show no increase in brush border NaDC-1 activity upon acid feeding. Using ETА/ETB chimeric constructs, ET-1 stimulation of NaDC-1 requires the receptor C-terminal tail (from either ETA or ETB) and is greatest with the ETB transmembrane domain plus a C-terminal tail.\",\n      \"method\": \"Pharmacological ETB antagonism in OKP cells, ETB knockout mouse model, brush border membrane vesicle NaDC-1 activity assay, ETА/ETB chimeric receptor constructs\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in vivo plus pharmacological and chimeric receptor approaches in vitro, replicated across model systems\",\n      \"pmids\": [\"20703215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SLC26A6 physically and functionally interacts with NaDC-1: the STAS domain of SLC26A6 and the first intracellular loop of NaDC-1 mediate their physical interaction (biochemical pull-down/co-expression) and functional cross-regulation. NaDC-1 enhances SLC26A6 transport activity, while SLC26A6 inhibits NaDC-1 transport activity in an activity-dependent manner. Slc26a6-null mice show increased renal/intestinal sodium-dependent succinate uptake and hypocitraturia, consistent with loss of SLC26A6-mediated NaDC-1 inhibition.\",\n      \"method\": \"Co-expression in Xenopus oocytes, Slc26a6-knockout mouse model, biochemical domain interaction analysis (STAS domain and NaDC-1 intracellular loop), transport assays\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional regulation shown in oocytes, physical interaction domain-mapped, validated in knockout mouse model\",\n      \"pmids\": [\"23833257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In normal human kidney, NaDC-1 (SLC13A2) protein localizes exclusively to the apical (luminal) membrane throughout the entire proximal tubule (including proximal convoluted and proximal straight tubule), co-localizing with NBCe1; NaDC-1 is not detectable in other renal cell types or in renal tumors (clear cell RCC, papillary RCC, oncocytoma, chromophobe carcinoma).\",\n      \"method\": \"Immunoblot (~61 kDa band), immunohistochemistry, colocalization with NBCe1 in human kidney tissue sections\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization in human tissue with colocalization marker, single lab\",\n      \"pmids\": [\"27927654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Acid stimulation of NaDC-1 activity requires Pyk2/c-Src and a Raf1-ERK1/2-p90RSK signaling cascade; these pathways are distinct from and not downstream of ET-1/ETB signaling. Pyk2-null mice fail to show NH4Cl-induced increase in brush border NaDC-1 activity; ERK1/2 phosphorylation by acid is Pyk2-independent; Raf1 and p90RSK inhibition blocks acid but not ET-1 stimulation of NaDC-1.\",\n      \"method\": \"Pyk2 and c-Src inhibition in OKP cells, Pyk2-knockout mice, NH4Cl loading, brush border vesicle NaDC-1 activity assay, immunoblot for pathway phosphorylation, [14C]-citrate uptake\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse plus pharmacological pathway dissection in two model systems with multiple orthogonal readouts\",\n      \"pmids\": [\"29678998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC13A2 promotes liver regeneration by importing citrate into hepatocytes, which serves as substrate for ACLY-dependent acetyl-CoA generation and de novo cholesterol biosynthesis via increased SREBP2 cleavage and upregulation of LDLR and HMGCR; ACLY inhibition or HMGCR inhibition (lovastatin) abrogates SLC13A2-mediated regeneration. Liver-specific overexpression promotes, and liver-specific depletion attenuates, liver regeneration after partial hepatectomy in mice.\",\n      \"method\": \"Partial hepatectomy mouse model, liver-specific SLC13A2 overexpression/knockout (AAV), metabolic flux analysis, ACLY inhibitor, lovastatin treatment, SREBP2 cleavage assay, cholesterol synthesis measurement\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-and-loss-of-function in vivo, metabolic flux analysis, and pathway inhibitor rescue in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"39824985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In hepatocellular carcinoma, SLC13A2-imported citrate generates acetyl-CoA that acetylates pyruvate kinase M2 (PKM2), triggering its degradation; reduced PKM2 activity limits pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. SLC13A2-imported citrate also increases intracellular protein acetylation (including histone acetylation), altering transcriptional regulation and contributing to tumor suppression. AAV-mediated liver-specific SLC13A2 knockout promotes, while overexpression ameliorates, HCC progression.\",\n      \"method\": \"AAV-mediated liver-specific knockout/overexpression in mouse HCC models, metabolic flux analysis, PKM2 acetylation and degradation assays, histone acetylation analysis, acetyl-CoA measurement\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with mechanistic biochemical assays in a single study, not yet independently replicated\",\n      \"pmids\": [\"41950310\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC13A2 (NaDC-1) is an apical membrane Na+/dicarboxylate cotransporter in renal proximal tubule that mediates electrogenic, sodium-coupled uptake of TCA cycle intermediates (citrate, succinate) with ≥3 Na+ per substrate; its activity is acutely downregulated via PKC-driven endocytosis, and chronically upregulated in metabolic acidosis through a signaling cascade requiring ETB receptor activation upstream of Pyk2/c-Src and Raf1-ERK1/2-p90RSK; SLC26A6 physically interacts with NaDC-1's first intracellular loop via its STAS domain to inhibit NaDC-1 activity, providing feedback regulation of oxalate/citrate homeostasis; beyond the kidney, SLC13A2-imported citrate fuels ACLY-dependent acetyl-CoA production for de novo cholesterol synthesis and protein/histone acetylation, with demonstrated roles in liver regeneration and tumor suppression in hepatocellular carcinoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC13A2 (NaDC-1) is an apical-membrane, sodium-coupled cotransporter of the renal proximal tubule that mediates electrogenic uptake of TCA-cycle dicarboxylates and tricarboxylates, providing a physiological route for citrate and succinate reabsorption [#0, #6, #10]. Transport is electrogenic and high-stoichiometry, with a Hill coefficient of ~2.9 for sodium indicating three Na+ co-transported per succinate, and shows pH-dependent citrate handling versus pH-insensitive succinate handling [#0, #7]. Systematic mutagenesis localized cation- and substrate-binding determinants to acidic residues Asp-373 (TM8) and Glu-475 (TM9) and to Lys-84 and Arg-349, while His-106 and multiple cysteines are required not for catalysis but for surface expression and trafficking [#1, #2, #3, #5]. Activity is acutely suppressed by PKC activation through endocytic removal and direct inhibition independent of consensus phosphorylation sites [#4], and is chronically upregulated in metabolic acidosis via increased apical protein abundance through two parallel signaling arms: an endothelin-1/ETB-receptor pathway and a Pyk2/c-Src \\u2013 Raf1-ERK1/2-p90RSK cascade [#6, #8, #11]. SLC13A2 is reciprocally regulated by SLC26A6, whose STAS domain binds the first intracellular loop of NaDC-1 to inhibit its transport and thereby couple citrate and oxalate handling [#9]. Beyond the kidney, SLC13A2-imported citrate fuels ACLY-dependent acetyl-CoA production for de novo cholesterol synthesis, driving hepatocyte proliferation during liver regeneration [#12], and supports protein and histone acetylation that promotes PKM2 acetylation/degradation and tumor suppression in hepatocellular carcinoma [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established NaDC-1 as a sodium-coupled di/tricarboxylate cotransporter and defined its core transport mechanism, answering what substrates and ion stoichiometry the protein uses.\",\n      \"evidence\": \"Heterologous expression in COS-7 cells with radiolabeled succinate/citrate uptake and Hill-coefficient kinetic analysis\",\n      \"pmids\": [\"8596711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the transport cycle\", \"pH-sensitivity mechanism for citrate versus succinate not defined at the residue level\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Distinguished residues needed for catalysis from those needed for surface delivery, showing His-106 governs trafficking rather than transport.\",\n      \"evidence\": \"Systematic mutagenesis of all 11 histidines with cell-surface biotinylation and succinate uptake in Xenopus oocytes\",\n      \"pmids\": [\"9512488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery interacting with His-106 not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped cation- and substrate-binding determinants to acidic transmembrane residues, building a topological picture of the binding site.\",\n      \"evidence\": \"Site-directed mutagenesis of acidic residues with two-electrode voltage clamp and uptake kinetics in oocytes\",\n      \"pmids\": [\"10360950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure to confirm residue geometry\", \"Reported anion-channel-like behavior of E475A not mechanistically resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed cysteines are collectively required for stability/trafficking rather than individually for transport, and identified pCMBS-accessible residues marking the aqueous transport pathway.\",\n      \"evidence\": \"Complete cysteine mutagenesis with pCMBS accessibility probing in oocytes\",\n      \"pmids\": [\"10548552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational states sampled by accessible cysteines not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined PKC as an acute negative regulator acting through endocytosis plus direct inhibition, independent of canonical phosphorylation sites.\",\n      \"evidence\": \"PKC/PKA pharmacology, phosphosite mutagenesis, surface protein quantification and cytochalasin D treatment in oocytes\",\n      \"pmids\": [\"10446305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of PKC if not direct phosphorylation of NaDC-1 unknown\", \"Endocytic adaptors not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified additional substrate-handling residues (Lys-84, Arg-349) refining the succinate-binding site.\",\n      \"evidence\": \"Site-directed mutagenesis with transport kinetics in oocytes\",\n      \"pmids\": [\"10970779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab kinetic inference without structural confirmation\", \"Distinct effects on succinate versus citrate not mechanistically explained\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated physiological regulation in vivo, showing metabolic acidosis raises apical NaDC-1 mRNA and protein in proximal tubule while alkali has no effect.\",\n      \"evidence\": \"Rat acidosis model with immunohistochemistry, brush-border immunoblot and mRNA quantification\",\n      \"pmids\": [\"10886565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway linking acidosis to expression not yet defined\", \"Segment-specific regulation mechanism unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed acid stimulation can occur post-transcriptionally, indicating regulation acts on protein activity/trafficking and not only transcription.\",\n      \"evidence\": \"OKP cell acidification with Na-dependent citrate uptake, GFP-tagged constructs, and oocyte characterization of the opossum ortholog\",\n      \"pmids\": [\"14973148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Post-transcriptional mechanism (stability vs trafficking) not resolved\", \"Reconciliation with transcriptional induction in vivo incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the ETB receptor as a required upstream node for acid stimulation, defining a receptor-level entry point to the regulatory cascade.\",\n      \"evidence\": \"ETB antagonism and ETA/ETB chimeras in OKP cells plus ETB-knockout mice with brush-border activity assays\",\n      \"pmids\": [\"20703215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors linking ETB to transporter at this stage unknown\", \"Source of acid-induced ET-1 not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined SLC26A6 as a direct physical and reciprocal functional regulator, coupling citrate and oxalate handling at the membrane.\",\n      \"evidence\": \"STAS-domain/intracellular-loop interaction mapping, oocyte co-expression, and Slc26a6-null mice with succinate uptake and citraturia readouts\",\n      \"pmids\": [\"23833257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STAS-loop binding not resolved\", \"Whether interaction is constitutive or regulated is unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the intracellular signaling cascade for acid stimulation as a Pyk2/c-Src and Raf1-ERK1/2-p90RSK pathway distinct from ETB signaling.\",\n      \"evidence\": \"Pyk2/c-Src inhibition in OKP cells, Pyk2-knockout mice, NH4Cl loading and brush-border activity assays with pathway phospho-immunoblots\",\n      \"pmids\": [\"29678998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How parallel ETB and Pyk2 arms converge on the transporter unknown\", \"Terminal step modifying NaDC-1 trafficking not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended SLC13A2 function beyond the kidney, showing citrate import feeds ACLY-dependent acetyl-CoA and cholesterol synthesis to drive liver regeneration.\",\n      \"evidence\": \"Partial hepatectomy with liver-specific AAV overexpression/knockout, metabolic flux analysis, and ACLY/HMGCR inhibitor rescue in mice\",\n      \"pmids\": [\"39824985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same citrate-acetyl-CoA axis operates in renal cells untested\", \"Regulation of hepatic SLC13A2 expression not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected SLC13A2 citrate import to acetylation-driven PKM2 degradation and histone acetylation, establishing a tumor-suppressive role in hepatocellular carcinoma.\",\n      \"evidence\": \"Liver-specific AAV knockout/overexpression in mouse HCC models with metabolic flux, PKM2 acetylation/degradation and histone acetylation assays\",\n      \"pmids\": [\"41950310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently replicated\", \"Acetyltransferase mediating PKM2 acetylation not identified\", \"Relevance to human HCC outcomes untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the parallel acidosis-sensing pathways (ETB and Pyk2/Raf-ERK-RSK) ultimately converge to modify NaDC-1 protein trafficking, and whether the hepatic citrate-acetyl-CoA functions generalize to kidney, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified terminal modification or adaptor that increases apical NaDC-1 abundance\", \"No structural model linking residue-level binding data to the transport cycle\", \"Cross-tissue unification of transport and metabolic roles incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SLC26A6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}