{"gene":"OXCT1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1996,"finding":"Human OXCT1 (SCOT) encodes a succinyl-CoA:3-oxoacid CoA transferase that catalyzes the rate-determining step of ketolysis (esterification of acetoacetate to CoA) in extrahepatic tissues; a homozygous nonsense mutation (S283X) abolishes enzyme function and causes hereditary SCOT deficiency with episodic ketoacidosis. The gene was mapped to chromosome 5p13 by in situ hybridization.","method":"cDNA cloning, in situ hybridization, mutation analysis in patient fibroblasts","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 — cDNA cloning, chromosomal mapping, and functional loss demonstrated by patient mutation; foundational paper with 51 citations","pmids":["8751852"],"is_preprint":false},{"year":2000,"finding":"The human OXCT1 gene spans >100 kb with 17 exons on chromosome 5p13. Homology modeling based on Acidaminococcus fermentans glutaconate CoA transferase predicted that V221 and G219 lie on the dimerizing surface while G324 is near the active site; transient expression of missense mutant cDNAs in SCOT-deficient fibroblasts confirmed that G219E and G324E abolish activity while V221M retains ~10% activity, consistent with the structural model.","method":"Gene cloning, homology structural modeling, transient expression assay in patient fibroblasts","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — structural model validated by functional transient expression assay with multiple mutants","pmids":["10964512"],"is_preprint":false},{"year":1997,"finding":"OXCT1 protein (SCOT) is detectable by immunoblot in control fibroblasts and lymphocytes but absent in fibroblasts and lymphocytes from SCOT-deficient patients, establishing immunoblot as a diagnostic tool and confirming complete loss of protein in null-mutation patients.","method":"Recombinant human SCOT expression in bacteria, antibody development, immunoblot analysis of patient and control cells","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal immunoblot in patient vs. control cells; single lab but orthogonal protein and activity measurements","pmids":["9128180"],"is_preprint":false},{"year":1998,"finding":"OXCT1 missense mutations V133E and C456F each abolish SCOT enzymatic activity when expressed in SCOT-deficient fibroblasts, whereas the co-occurring T58M substitution is functionally neutral, demonstrating allele-specific pathogenicity through transient expression.","method":"Transient expression of mutant cDNAs in immortalized SCOT-deficient fibroblasts, SCOT activity assay","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 — in vitro functional reconstitution with mutagenesis in patient cell background","pmids":["9671268"],"is_preprint":false},{"year":2002,"finding":"A testis-specific paralog of OXCT1, human Scot-t (OXCT2), is encoded by an intronless gene located within an intron of BMP8 on chromosome 1p34.1-35.3, and its protein localizes to the mitochondria-rich midpiece of ejaculated spermatozoa, suggesting a role in ketone body-based energy metabolism in sperm.","method":"cDNA cloning, PCR-based genomic structure analysis, subcellular localization by immunostaining of spermatozoa","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment linked to functional context; single lab","pmids":["11756565"],"is_preprint":false},{"year":2003,"finding":"In mouse testis, the somatic SCOT isoform (scot-s/OXCT1) is expressed exclusively in Leydig and Sertoli cells, whereas the germline isoform (scot-t) is expressed in germ cells; SCOT enzymatic activity in sperm (from scot-t) is 2.5-fold higher than in Leydig cells, indicating cell-type-specific isoform utilization for ketone body metabolism.","method":"Differential RT-PCR, enzymatic activity assay in Leydig cell and sperm fractions","journal":"International journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 — direct fractionation and enzymatic assay in defined cell populations","pmids":["12534938"],"is_preprint":false},{"year":2004,"finding":"The T435N mutation in OXCT1 retains significant residual SCOT activity (~20-50% depending on temperature) and is temperature-sensitive, explaining why patients homozygous for T435N develop ketoacidotic crises during febrile illness but lack permanent ketosis. Residual activity is more vulnerable to heat treatment than wild-type.","method":"Transient expression of mutant cDNA in SCOT-deficient fibroblasts, SCOT activity assay at multiple temperatures, heat-treatment stability assay","journal":"Pediatric research","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution with temperature-dependent activity and stability measurements","pmids":["15496607"],"is_preprint":false},{"year":2007,"finding":"The R268H OXCT1 mutation produces a temperature-sensitive protein: residual SCOT activity is 59.7%, 34%, and 4% when expressed at 30°C, 37°C, and 40°C, respectively. Three-dimensional structural analysis indicates R268 forms a conserved salt bridge with D52; disruption of this bridge destabilizes the protein in a temperature-dependent manner.","method":"Transient expression at multiple temperatures, heat-treatment stability assay, 3D structural analysis","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution at multiple temperatures combined with structural analysis","pmids":["17706444"],"is_preprint":false},{"year":2010,"finding":"In diabetic db/db mouse heart mitochondria, SCOT (OXCT1) is nitrated at Tyr4 and Tyr76 by peroxynitrite. Site-directed mutagenesis of either tyrosine protects SCOT from peroxynitrite modification and prevents loss of enzymatic activity, establishing these residues as the priority nitration sites that causally inhibit SCOT catalysis.","method":"Recombinant SCOT incubation with peroxynitrite, LC-ESI-MS/MS identification of nitrated residues, site-directed mutagenesis, activity assay","journal":"Journal of proteome research","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with peroxynitrite, mass-spectrometric site identification, and mutagenesis confirmation; multiple orthogonal methods","pmids":["20527992"],"is_preprint":false},{"year":2010,"finding":"OXCT1 (SCOT) knockdown by shRNA in INS-1 832/13 pancreatic beta-cells reduces glucose- or methyl succinate+β-hydroxybutyrate-stimulated insulin release by >70%, demonstrating that OXCT1-dependent mitochondrial acetoacetate export is required for normal insulin secretion.","method":"shRNA knockdown in insulinoma cell line, enzymatic activity confirmation, insulin secretion assay","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 2 — clean KD with dose-response across multiple cell lines plus defined functional readout","pmids":["20460097"],"is_preprint":false},{"year":2011,"finding":"Multiple OXCT1 missense mutations (L327P, R468C, A215V, S226N) exhibit residual activity or temperature-sensitive stability; structural prediction indicates main effects are destabilization of the SCOT dimer or disruption of catalytic activity. Expression at 30°C vs. 37°C rescues some mutant protein levels, confirming temperature-sensitive character.","method":"Transient expression of mutant cDNAs, immunoblot, SCOT activity assay at 30°C and 37°C","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — multi-mutant functional characterization with structural prediction, replicated across five patient alleles","pmids":["21296660"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of human SCOT (OXCT1) was determined, providing molecular understanding of disease-causing mutations: mutations cluster in regions affecting protein stability or active-site geometry, enabling structure-based classification of all reported pathogenic OXCT1 alleles.","method":"X-ray crystallography of human SCOT protein","journal":"Journal of inherited metabolic disease","confidence":"High","confidence_rationale":"Tier 1 — crystal structure determination with functional mutation mapping","pmids":["23420214"],"is_preprint":false},{"year":2013,"finding":"A splice-site mutation (c.1248+5g>a) in OXCT1 causes simultaneous skipping of exons 12 and 13 through a 'splicing paralysis' mechanism: the mutation retains intron 13, which in turn prevents removal of introns 12 and 11; the entire intron11-exon12-intron12-exon13-mutant intron13 unit is then skipped, producing a frame-retaining mRNA that escapes nonsense-mediated decay.","method":"RT-PCR of heteronuclear RNA intermediates from patient vs. control fibroblasts, comparison of intron removal order","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dissection of splicing pathway using hnRNA intermediates; single lab","pmids":["23281106"],"is_preprint":false},{"year":2022,"finding":"Frataxin physically interacts with OXCT1 both in vivo and in vitro, and frataxin overexpression increases OXCT1 protein levels while frataxin deficiency decreases OXCT1 across multiple cell types. Frataxin suppresses ubiquitin-proteasome system (UPS)-dependent degradation of OXCT1, thereby regulating ketone body metabolism; frataxin-deficient cells fail to convert ketone bodies to acetyl-CoA.","method":"Co-immunoprecipitation in vivo and in vitro, frataxin overexpression/knockdown in human fibroblasts and knock-in/knockout mice, UPS inhibitor rescue, ketone body metabolite quantification","journal":"PNAS nexus","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP in vivo and in vitro, multiple cell types, mechanistic rescue experiment; multiple orthogonal methods","pmids":["36016708"],"is_preprint":false},{"year":2024,"finding":"OXCT1 functions as a lysine succinyltransferase in addition to its ketolytic role: residue G424 is essential for succinyltransferase activity. OXCT1 directly succinylates LACTB at K284, which inhibits LACTB proteolytic activity, leading to increased mitochondrial membrane potential and respiration and promoting HCC progression.","method":"In vitro succinyltransferase assay, site-directed mutagenesis (G424), identification of LACTB as substrate by MS and Co-IP, LACTB K284 succinylation functional assay, mitochondrial membrane potential and respiration measurements","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic reconstitution, mutagenesis of active site residue, substrate identification by MS/Co-IP, functional validation of succinylation site","pmids":["38176415"],"is_preprint":false},{"year":2024,"finding":"In HCC cells, IGF1 stimulation triggers ERK2-mediated phosphorylation of SUCLA2 at S124, followed by PIN1-mediated cis-trans isomerization of SUCLA2, enabling SUCLA2 to interact with OXCT1. SUCLA2-associated OXCT1 is then succinylated at K421, which activates OXCT1 enzymatic activity, substantially enhancing ketolysis and tumor growth.","method":"Co-IP of OXCT1-SUCLA2 complex, phospho-mutant and isomerization-deficient constructs, K421 succinylation site mutagenesis, in vitro ketolysis assay, mouse tumor models, acetohydroxamic acid inhibitor treatment","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted interaction cascade with multiple mutants, enzymatic readout, and in vivo validation","pmids":["39862868"],"is_preprint":false},{"year":2024,"finding":"OXCT1 deficiency in tumor-associated macrophages (TAMs) suppresses tumor growth by reducing succinate accumulation; high OXCT1-driven ketolysis generates succinate that increases H3K4me3 at the Arg1 promoter, promoting Arg1 transcription, TAM polarization to a protumor phenotype, and CD8+ T-cell exhaustion.","method":"LysMcre-OXCT1f/f conditional knockout mice, multiplex immunohistochemistry, ChIP-seq/H3K4me3 measurement at Arg1 promoter, succinate metabolite quantification, CD8+ T-cell functional assays","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — macrophage-specific genetic KO with multiple mechanistic readouts (epigenetic, metabolic, immunological)","pmids":["38759889"],"is_preprint":false},{"year":2023,"finding":"After traumatic brain injury (TBI), OXCT1 expression decreases in hippocampal neurons; adeno-associated virus-mediated OXCT1 overexpression increases SIRT3 expression and reduces acetylated SOD2, thereby decreasing reactive oxygen species production in injured hippocampal neurons, reducing neuronal death, and improving cognitive function.","method":"AAV-mediated OXCT1 overexpression in mice, TBI weight-drop model, immunoblot for SIRT3 and acetyl-SOD2, DHE staining for ROS, Nissl staining for neuronal death, cognitive behavioral tests","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain-of-function with defined molecular (SIRT3/SOD2) and functional (ROS, cognition) readouts; single lab","pmids":["36921750"],"is_preprint":false},{"year":2024,"finding":"OXCT1 overexpression in hippocampal neurons after subarachnoid hemorrhage activates the Akt/GSK-3β/β-catenin signaling pathway to promote adult hippocampal neurogenesis; this effect is abolished by the PI3K inhibitor LY294002, placing OXCT1-dependent ketone metabolism upstream of Akt signaling in neurogenesis.","method":"AAV-mediated OXCT1 overexpression in SAH mouse model, LY294002 pharmacological inhibition, doublecortin/EdU dual staining for neurogenesis, immunofluorescence and immunoblot for Akt/GSK-3β/β-catenin, Morris water maze and Y-maze","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via pharmacological inhibitor plus gain-of-function with defined pathway and functional readout; single lab","pmids":["38199308"],"is_preprint":false},{"year":2025,"finding":"OXCT1 succinylates PGK1 at K146, increasing PGK1 protein stability (reducing its ubiquitination without affecting mRNA), thereby enhancing aerobic glycolysis and PD-L1 expression to promote immune escape in triple-negative breast cancer. KMT5A methyltransferase increases H4K20me1 at the OXCT1 promoter to drive OXCT1 expression upstream.","method":"OXCT1 overexpression/knockdown in TNBC cells and patient-derived organoids, succinylation site mapping (PGK1 K146), ubiquitination assay, KMT5A ChIP for H4K20me1 at OXCT1 promoter, T-cell killing assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with succinylation site mapping and upstream epigenetic regulation; single lab","pmids":["40634657"],"is_preprint":false},{"year":2019,"finding":"OXCT1 knockdown in ovine preadipocytes promotes lipid accumulation, while overexpression reduces it, demonstrating that OXCT1 negatively regulates adipogenesis/lipid deposition in adipocytes.","method":"OXCT1 siRNA knockdown and overexpression in ovine adipocytes, lipid accumulation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, KD/OE with phenotypic readout but no downstream pathway placement","pmids":["30928098"],"is_preprint":false},{"year":2021,"finding":"OXCT1 overexpression in PDAC cells promotes gemcitabine resistance by activating the NF-κB signaling pathway; an NF-κB inhibitor reverses OXCT1-mediated gemcitabine resistance both in vitro and in mouse tumor models.","method":"OXCT1 overexpression/knockdown in PDAC cell lines, NF-κB inhibitor rescue, GSEA pathway analysis, mouse xenograft tumor models, apoptosis assay","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis (NF-κB inhibitor reversal) with in vivo validation; single lab","pmids":["34804914"],"is_preprint":false}],"current_model":"OXCT1 encodes the mitochondrial succinyl-CoA:3-oxoacid CoA transferase (SCOT) that catalyzes the rate-limiting step of ketolysis in extrahepatic tissues; beyond this canonical role, OXCT1 also acts as a lysine succinyltransferase (requiring residue G424) that succinylates substrates such as LACTB (inhibiting its protease activity) and PGK1 (stabilizing it), and is itself activated by SUCLA2-mediated K421 succinylation downstream of IGF1/ERK2/PIN1 signaling; its protein stability is regulated by frataxin-dependent suppression of ubiquitin-proteasome degradation, its catalytic activity is inhibited by peroxynitrite-mediated nitration at Y4 and Y76, and it participates in neuronal neuroprotection via SIRT3-SOD2 and Akt/GSK-3β/β-catenin pathways, as well as in macrophage immunometabolism through succinate-driven epigenetic regulation of Arg1."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing OXCT1 as the gene encoding SCOT and linking its loss to hereditary ketoacidosis answered the fundamental question of what enzyme catalyzes the rate-limiting step of ketolysis in extrahepatic tissues.","evidence":"cDNA cloning, chromosomal mapping to 5p13, and identification of homozygous S283X nonsense mutation in SCOT-deficient patient fibroblasts","pmids":["8751852"],"confidence":"High","gaps":["enzymatic mechanism and active-site architecture not yet resolved","tissue-specific expression pattern not systematically characterized"]},{"year":1998,"claim":"Functional expression of patient-derived missense alleles in SCOT-deficient cells established the principle that individual residues (V133, C456) are essential for catalytic activity while others (T58) are neutral, enabling genotype-phenotype correlation.","evidence":"Transient expression of V133E, C456F, and T58M mutant cDNAs in immortalized SCOT-deficient fibroblasts with activity assay","pmids":["9671268"],"confidence":"High","gaps":["no crystal structure to rationalize why specific residues are essential","incomplete allelic series"]},{"year":2000,"claim":"Determining the full genomic structure (17 exons, >100 kb) and using homology modeling to predict dimerization and active-site residues—validated by mutagenesis—provided the first structural framework for understanding SCOT function.","evidence":"Gene cloning, homology modeling against A. fermentans glutaconate CoA transferase, transient expression of G219E, V221M, G324E mutants","pmids":["10964512"],"confidence":"High","gaps":["homology model not experimentally validated by crystallography","dimerization interface not confirmed by biophysical methods"]},{"year":2004,"claim":"Discovery that the T435N and later R268H mutations are temperature-sensitive explained the clinical observation that febrile illness triggers ketoacidotic crises in patients with residual SCOT activity, revealing protein stability as a disease-modifying factor.","evidence":"Transient expression at 30°C, 37°C, and 40°C with heat-treatment stability assays; 3D structural analysis of the R268-D52 salt bridge","pmids":["15496607","17706444"],"confidence":"High","gaps":["no in vivo confirmation of temperature sensitivity in animal models","folding intermediates and chaperone dependencies not characterized"]},{"year":2010,"claim":"Identification of Y4 and Y76 as peroxynitrite-nitration sites that causally inhibit SCOT activity in diabetic heart mitochondria established a post-translational mechanism for OXCT1 inactivation in metabolic disease.","evidence":"Recombinant SCOT treated with peroxynitrite, LC-ESI-MS/MS site identification, Y4F/Y76F mutagenesis protecting activity","pmids":["20527992"],"confidence":"High","gaps":["in vivo relevance of nitration in diabetic cardiomyopathy not directly tested","whether nitration is reversible or irreversible in cells is unknown"]},{"year":2010,"claim":"OXCT1 knockdown in beta-cells demonstrated that SCOT-dependent ketone body metabolism is required for normal glucose- and metabolite-stimulated insulin secretion, extending its role beyond simple fuel oxidation.","evidence":"shRNA knockdown in INS-1 832/13 insulinoma cells with insulin secretion assay","pmids":["20460097"],"confidence":"High","gaps":["mechanism linking OXCT1 to insulin granule exocytosis not defined","not confirmed in primary islets or in vivo"]},{"year":2013,"claim":"The crystal structure of human SCOT enabled structure-based classification of all known pathogenic alleles, resolving whether mutations affect stability, dimerization, or catalysis.","evidence":"X-ray crystallography of human SCOT with mapping of disease mutations","pmids":["23420214"],"confidence":"High","gaps":["no co-crystal with substrate or CoA intermediate","conformational dynamics during catalysis not captured"]},{"year":2022,"claim":"Discovery that frataxin physically interacts with OXCT1 and protects it from ubiquitin-proteasome degradation revealed a new layer of OXCT1 regulation and connected Friedreich's ataxia pathophysiology to impaired ketolysis.","evidence":"Reciprocal co-IP in vivo and in vitro, frataxin OE/KD across human fibroblasts and mouse models, proteasome inhibitor rescue, ketone body metabolite quantification","pmids":["36016708"],"confidence":"High","gaps":["E3 ubiquitin ligase responsible for OXCT1 degradation not identified","structural basis of frataxin-OXCT1 interaction unknown"]},{"year":2023,"claim":"OXCT1 overexpression after traumatic brain injury showed that OXCT1-dependent ketone metabolism activates the SIRT3-SOD2 axis to reduce ROS and neuronal death, positioning OXCT1 as a neuroprotective factor.","evidence":"AAV-mediated OXCT1 overexpression in mouse TBI model, immunoblot for SIRT3/acetyl-SOD2, ROS quantification, cognitive behavioral tests","pmids":["36921750"],"confidence":"Medium","gaps":["whether SIRT3 activation is a direct or indirect consequence of enhanced ketolysis is unclear","loss-of-function approach not performed in this system"]},{"year":2024,"claim":"The revelation that OXCT1 possesses intrinsic lysine succinyltransferase activity (dependent on G424) that succinylates LACTB to inhibit its protease function fundamentally expanded the enzyme's functional repertoire beyond ketolysis.","evidence":"In vitro succinyltransferase assay, G424 mutagenesis, LACTB K284 succinylation mapping by MS and Co-IP, mitochondrial respiration measurements","pmids":["38176415"],"confidence":"High","gaps":["full substrate scope of OXCT1 succinyltransferase activity unknown","structural basis for dual catalytic activities not resolved"]},{"year":2024,"claim":"Mapping the IGF1→ERK2→SUCLA2(S124 phosphorylation)→PIN1→SUCLA2-OXCT1 interaction→K421 succinylation cascade showed how growth factor signaling activates OXCT1 ketolytic activity to fuel tumor growth.","evidence":"Co-IP of OXCT1-SUCLA2, phospho- and isomerization-deficient mutants, K421 mutagenesis, in vitro ketolysis assay, mouse tumor models","pmids":["39862868"],"confidence":"High","gaps":["whether K421 succinylation also affects succinyltransferase activity is untested","desuccinylase(s) reversing K421 modification not identified"]},{"year":2024,"claim":"Macrophage-specific OXCT1 knockout demonstrated that OXCT1-driven succinate accumulation epigenetically activates Arg1 via H3K4me3, promoting protumor macrophage polarization and CD8+ T-cell exhaustion.","evidence":"LysMcre-OXCT1f/f conditional KO mice, ChIP-seq for H3K4me3 at Arg1 promoter, succinate metabolomics, CD8+ T-cell functional assays","pmids":["38759889"],"confidence":"High","gaps":["which histone methyltransferase is recruited by succinate accumulation not identified","generalizability beyond liver cancer TAMs not established"]},{"year":2025,"claim":"Identification of PGK1 K146 as a second OXCT1 succinyltransferase substrate that stabilizes PGK1 protein and promotes glycolysis/PD-L1-mediated immune evasion broadened the oncogenic scope of OXCT1's non-canonical activity.","evidence":"Succinylation site mapping on PGK1, ubiquitination assay, KMT5A ChIP for H4K20me1 at OXCT1 promoter, T-cell killing assay in TNBC cells and PDOs","pmids":["40634657"],"confidence":"Medium","gaps":["whether PGK1 succinylation occurs in non-cancer contexts is unknown","OXCT1 succinyltransferase activity has not been reconstituted with purified components for PGK1"]},{"year":null,"claim":"Key unresolved questions include the full substrate repertoire of OXCT1's succinyltransferase activity, the structural basis for its dual enzymatic functions, the identity of the E3 ligase mediating OXCT1 proteasomal turnover, and whether the non-canonical activities operate in normal physiology or are cancer-specific.","evidence":"","pmids":[],"confidence":"Low","gaps":["no structural model of succinyltransferase active site or dual-function mechanism","E3 ubiquitin ligase for OXCT1 degradation not identified","succinyltransferase substrate scope not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,3,6,7,8,14,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[14,19]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,4,8,14]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,9,14,15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,15,16,19,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14,15,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16]}],"complexes":["SCOT homodimer"],"partners":["SUCLA2","FXN","LACTB","PGK1","ERK2","PIN1"],"other_free_text":[]},"mechanistic_narrative":"OXCT1 encodes the mitochondrial succinyl-CoA:3-oxoacid CoA transferase (SCOT) that catalyzes the rate-limiting step of extrahepatic ketolysis by transferring CoA from succinyl-CoA to acetoacetate, and loss-of-function mutations cause hereditary SCOT deficiency with episodic ketoacidosis [PMID:8751852, PMID:10964512]. Beyond its canonical ketolytic activity, OXCT1 functions as a lysine succinyltransferase—dependent on residue G424—that succinylates substrates including LACTB (inhibiting its protease activity to enhance mitochondrial respiration) and PGK1 (stabilizing the protein to promote glycolysis), linking OXCT1 to hepatocellular carcinoma and breast cancer progression [PMID:38176415, PMID:40634657]. OXCT1 catalytic activity is itself regulated by SUCLA2-mediated succinylation at K421 downstream of IGF1/ERK2/PIN1 signaling, by frataxin-dependent suppression of proteasomal degradation, and by inhibitory peroxynitrite-mediated nitration at Y4 and Y76 [PMID:39862868, PMID:36016708, PMID:20527992]. In macrophages, OXCT1-driven ketolysis generates succinate that increases H3K4me3 at the Arg1 promoter to promote protumor polarization, while in neurons OXCT1 overexpression confers neuroprotection via the SIRT3-SOD2 and Akt/GSK-3β/β-catenin pathways [PMID:38759889, PMID:36921750, PMID:38199308]."},"prefetch_data":{"uniprot":{"accession":"P55809","full_name":"Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial","aliases":["3-oxoacid CoA-transferase 1","Somatic-type succinyl-CoA:3-oxoacid CoA-transferase","SCOT-s","Succinyl-CoA:3-oxoacid CoA transferase"],"length_aa":520,"mass_kda":56.2,"function":"Key enzyme for ketone body catabolism. Catalyzes the first, rate-limiting step of ketone body utilization in extrahepatic tissues, by transferring coenzyme A (CoA) from a donor thiolester species (succinyl-CoA) to an acceptor carboxylate (acetoacetate), and produces acetoacetyl-CoA. Acetoacetyl-CoA is further metabolized by acetoacetyl-CoA thiolase into two acetyl-CoA molecules which enter the citric acid cycle for energy production (PubMed:10964512). Forms a dimeric enzyme where both of the subunits are able to form enzyme-CoA thiolester intermediates, but only one subunit is competent to transfer the CoA moiety to the acceptor carboxylate (3-oxo acid) and produce a new acyl-CoA. Formation of the enzyme-CoA intermediate proceeds via an unstable anhydride species formed between the carboxylate groups of the enzyme and substrate (By similarity)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/P55809/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OXCT1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OXCT1","total_profiled":1310},"omim":[{"mim_id":"610289","title":"3-@OXOACID CoA TRANSFERASE 2; OXCT2","url":"https://www.omim.org/entry/610289"},{"mim_id":"601424","title":"3-@OXOACID CoA TRANSFERASE 1; OXCT1","url":"https://www.omim.org/entry/601424"},{"mim_id":"245050","title":"SUCCINYL-CoA:3-OXOACID-CoA TRANSFERASE DEFICIENCY; SCOTD","url":"https://www.omim.org/entry/245050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":230.2}],"url":"https://www.proteinatlas.org/search/OXCT1"},"hgnc":{"alias_symbol":["SCOT"],"prev_symbol":["OXCT"]},"alphafold":{"accession":"P55809","domains":[{"cath_id":"3.40.1080.10","chopping":"40-153_202-270","consensus_level":"high","plddt":97.9122,"start":40,"end":270},{"cath_id":"3.40.1080.10","chopping":"298-513","consensus_level":"high","plddt":96.3777,"start":298,"end":513}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55809","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55809-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55809-F1-predicted_aligned_error_v6.png","plddt_mean":91.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OXCT1","jax_strain_url":"https://www.jax.org/strain/search?query=OXCT1"},"sequence":{"accession":"P55809","fasta_url":"https://rest.uniprot.org/uniprotkb/P55809.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55809/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55809"}},"corpus_meta":[{"pmid":"26824445","id":"PMC_26824445","title":"Immunosuppressive 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England)","url":"https://pubmed.ncbi.nlm.nih.gov/31742326","citation_count":6,"is_preprint":false},{"pmid":"38199308","id":"PMC_38199308","title":"OXCT1 regulates hippocampal neurogenesis and alleviates cognitive impairment via the Akt/GSK-3β/β-catenin pathway after subarachnoid hemorrhage.","date":"2024","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/38199308","citation_count":5,"is_preprint":false},{"pmid":"36553602","id":"PMC_36553602","title":"Ploidy Status, Nuclear DNA Content and Start Codon Targeted (SCoT) Genetic Homogeneity Assessment in Digitalis purpurea L., Regenerated In Vitro.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36553602","citation_count":5,"is_preprint":false},{"pmid":"22301269","id":"PMC_22301269","title":"Identification of ORF sequences and exercise-induced expression change in thoroughbred horse OXCT1 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Miers Using Novel g-SSR Markers and Their Comparison with EST-SSR and SCoT Markers for Genetic Diversity Study.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36360279","citation_count":3,"is_preprint":false},{"pmid":"37126122","id":"PMC_37126122","title":"Impacts of ZnO as a nanofertilizer on fenugreek: some biochemical parameters and SCoT analysis.","date":"2023","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37126122","citation_count":3,"is_preprint":false},{"pmid":"38570817","id":"PMC_38570817","title":"Assessment of genetic homogeneity of in-vitro propagated apple root stock MM 104 using ISSR and SCoT primers.","date":"2024","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/38570817","citation_count":3,"is_preprint":false},{"pmid":"40731106","id":"PMC_40731106","title":"Unveiling genetic diversity and population structure in lentil (Lens culinaris) germplasm through scot markers.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40731106","citation_count":3,"is_preprint":false},{"pmid":"38958296","id":"PMC_38958296","title":"Protective Effect of Long Noncoding RNA OXCT1-AS1 on Doxorubicin-Induced Apoptosis of Human Myocardial Cells by the Competitive Endogenous RNA Pattern.","date":"2024","source":"Arquivos brasileiros de cardiologia","url":"https://pubmed.ncbi.nlm.nih.gov/38958296","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51618,"output_tokens":5435,"usd":0.11819},"stage2":{"model":"claude-opus-4-6","input_tokens":9026,"output_tokens":3363,"usd":0.193807},"total_usd":0.311997,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Human OXCT1 (SCOT) encodes a succinyl-CoA:3-oxoacid CoA transferase that catalyzes the rate-determining step of ketolysis (esterification of acetoacetate to CoA) in extrahepatic tissues; a homozygous nonsense mutation (S283X) abolishes enzyme function and causes hereditary SCOT deficiency with episodic ketoacidosis. The gene was mapped to chromosome 5p13 by in situ hybridization.\",\n      \"method\": \"cDNA cloning, in situ hybridization, mutation analysis in patient fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA cloning, chromosomal mapping, and functional loss demonstrated by patient mutation; foundational paper with 51 citations\",\n      \"pmids\": [\"8751852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human OXCT1 gene spans >100 kb with 17 exons on chromosome 5p13. Homology modeling based on Acidaminococcus fermentans glutaconate CoA transferase predicted that V221 and G219 lie on the dimerizing surface while G324 is near the active site; transient expression of missense mutant cDNAs in SCOT-deficient fibroblasts confirmed that G219E and G324E abolish activity while V221M retains ~10% activity, consistent with the structural model.\",\n      \"method\": \"Gene cloning, homology structural modeling, transient expression assay in patient fibroblasts\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural model validated by functional transient expression assay with multiple mutants\",\n      \"pmids\": [\"10964512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"OXCT1 protein (SCOT) is detectable by immunoblot in control fibroblasts and lymphocytes but absent in fibroblasts and lymphocytes from SCOT-deficient patients, establishing immunoblot as a diagnostic tool and confirming complete loss of protein in null-mutation patients.\",\n      \"method\": \"Recombinant human SCOT expression in bacteria, antibody development, immunoblot analysis of patient and control cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal immunoblot in patient vs. control cells; single lab but orthogonal protein and activity measurements\",\n      \"pmids\": [\"9128180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"OXCT1 missense mutations V133E and C456F each abolish SCOT enzymatic activity when expressed in SCOT-deficient fibroblasts, whereas the co-occurring T58M substitution is functionally neutral, demonstrating allele-specific pathogenicity through transient expression.\",\n      \"method\": \"Transient expression of mutant cDNAs in immortalized SCOT-deficient fibroblasts, SCOT activity assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro functional reconstitution with mutagenesis in patient cell background\",\n      \"pmids\": [\"9671268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A testis-specific paralog of OXCT1, human Scot-t (OXCT2), is encoded by an intronless gene located within an intron of BMP8 on chromosome 1p34.1-35.3, and its protein localizes to the mitochondria-rich midpiece of ejaculated spermatozoa, suggesting a role in ketone body-based energy metabolism in sperm.\",\n      \"method\": \"cDNA cloning, PCR-based genomic structure analysis, subcellular localization by immunostaining of spermatozoa\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment linked to functional context; single lab\",\n      \"pmids\": [\"11756565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In mouse testis, the somatic SCOT isoform (scot-s/OXCT1) is expressed exclusively in Leydig and Sertoli cells, whereas the germline isoform (scot-t) is expressed in germ cells; SCOT enzymatic activity in sperm (from scot-t) is 2.5-fold higher than in Leydig cells, indicating cell-type-specific isoform utilization for ketone body metabolism.\",\n      \"method\": \"Differential RT-PCR, enzymatic activity assay in Leydig cell and sperm fractions\",\n      \"journal\": \"International journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation and enzymatic assay in defined cell populations\",\n      \"pmids\": [\"12534938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The T435N mutation in OXCT1 retains significant residual SCOT activity (~20-50% depending on temperature) and is temperature-sensitive, explaining why patients homozygous for T435N develop ketoacidotic crises during febrile illness but lack permanent ketosis. Residual activity is more vulnerable to heat treatment than wild-type.\",\n      \"method\": \"Transient expression of mutant cDNA in SCOT-deficient fibroblasts, SCOT activity assay at multiple temperatures, heat-treatment stability assay\",\n      \"journal\": \"Pediatric research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution with temperature-dependent activity and stability measurements\",\n      \"pmids\": [\"15496607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The R268H OXCT1 mutation produces a temperature-sensitive protein: residual SCOT activity is 59.7%, 34%, and 4% when expressed at 30°C, 37°C, and 40°C, respectively. Three-dimensional structural analysis indicates R268 forms a conserved salt bridge with D52; disruption of this bridge destabilizes the protein in a temperature-dependent manner.\",\n      \"method\": \"Transient expression at multiple temperatures, heat-treatment stability assay, 3D structural analysis\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution at multiple temperatures combined with structural analysis\",\n      \"pmids\": [\"17706444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In diabetic db/db mouse heart mitochondria, SCOT (OXCT1) is nitrated at Tyr4 and Tyr76 by peroxynitrite. Site-directed mutagenesis of either tyrosine protects SCOT from peroxynitrite modification and prevents loss of enzymatic activity, establishing these residues as the priority nitration sites that causally inhibit SCOT catalysis.\",\n      \"method\": \"Recombinant SCOT incubation with peroxynitrite, LC-ESI-MS/MS identification of nitrated residues, site-directed mutagenesis, activity assay\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with peroxynitrite, mass-spectrometric site identification, and mutagenesis confirmation; multiple orthogonal methods\",\n      \"pmids\": [\"20527992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"OXCT1 (SCOT) knockdown by shRNA in INS-1 832/13 pancreatic beta-cells reduces glucose- or methyl succinate+β-hydroxybutyrate-stimulated insulin release by >70%, demonstrating that OXCT1-dependent mitochondrial acetoacetate export is required for normal insulin secretion.\",\n      \"method\": \"shRNA knockdown in insulinoma cell line, enzymatic activity confirmation, insulin secretion assay\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with dose-response across multiple cell lines plus defined functional readout\",\n      \"pmids\": [\"20460097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Multiple OXCT1 missense mutations (L327P, R468C, A215V, S226N) exhibit residual activity or temperature-sensitive stability; structural prediction indicates main effects are destabilization of the SCOT dimer or disruption of catalytic activity. Expression at 30°C vs. 37°C rescues some mutant protein levels, confirming temperature-sensitive character.\",\n      \"method\": \"Transient expression of mutant cDNAs, immunoblot, SCOT activity assay at 30°C and 37°C\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multi-mutant functional characterization with structural prediction, replicated across five patient alleles\",\n      \"pmids\": [\"21296660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of human SCOT (OXCT1) was determined, providing molecular understanding of disease-causing mutations: mutations cluster in regions affecting protein stability or active-site geometry, enabling structure-based classification of all reported pathogenic OXCT1 alleles.\",\n      \"method\": \"X-ray crystallography of human SCOT protein\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determination with functional mutation mapping\",\n      \"pmids\": [\"23420214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A splice-site mutation (c.1248+5g>a) in OXCT1 causes simultaneous skipping of exons 12 and 13 through a 'splicing paralysis' mechanism: the mutation retains intron 13, which in turn prevents removal of introns 12 and 11; the entire intron11-exon12-intron12-exon13-mutant intron13 unit is then skipped, producing a frame-retaining mRNA that escapes nonsense-mediated decay.\",\n      \"method\": \"RT-PCR of heteronuclear RNA intermediates from patient vs. control fibroblasts, comparison of intron removal order\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of splicing pathway using hnRNA intermediates; single lab\",\n      \"pmids\": [\"23281106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Frataxin physically interacts with OXCT1 both in vivo and in vitro, and frataxin overexpression increases OXCT1 protein levels while frataxin deficiency decreases OXCT1 across multiple cell types. Frataxin suppresses ubiquitin-proteasome system (UPS)-dependent degradation of OXCT1, thereby regulating ketone body metabolism; frataxin-deficient cells fail to convert ketone bodies to acetyl-CoA.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro, frataxin overexpression/knockdown in human fibroblasts and knock-in/knockout mice, UPS inhibitor rescue, ketone body metabolite quantification\",\n      \"journal\": \"PNAS nexus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in vivo and in vitro, multiple cell types, mechanistic rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"36016708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OXCT1 functions as a lysine succinyltransferase in addition to its ketolytic role: residue G424 is essential for succinyltransferase activity. OXCT1 directly succinylates LACTB at K284, which inhibits LACTB proteolytic activity, leading to increased mitochondrial membrane potential and respiration and promoting HCC progression.\",\n      \"method\": \"In vitro succinyltransferase assay, site-directed mutagenesis (G424), identification of LACTB as substrate by MS and Co-IP, LACTB K284 succinylation functional assay, mitochondrial membrane potential and respiration measurements\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic reconstitution, mutagenesis of active site residue, substrate identification by MS/Co-IP, functional validation of succinylation site\",\n      \"pmids\": [\"38176415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In HCC cells, IGF1 stimulation triggers ERK2-mediated phosphorylation of SUCLA2 at S124, followed by PIN1-mediated cis-trans isomerization of SUCLA2, enabling SUCLA2 to interact with OXCT1. SUCLA2-associated OXCT1 is then succinylated at K421, which activates OXCT1 enzymatic activity, substantially enhancing ketolysis and tumor growth.\",\n      \"method\": \"Co-IP of OXCT1-SUCLA2 complex, phospho-mutant and isomerization-deficient constructs, K421 succinylation site mutagenesis, in vitro ketolysis assay, mouse tumor models, acetohydroxamic acid inhibitor treatment\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted interaction cascade with multiple mutants, enzymatic readout, and in vivo validation\",\n      \"pmids\": [\"39862868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OXCT1 deficiency in tumor-associated macrophages (TAMs) suppresses tumor growth by reducing succinate accumulation; high OXCT1-driven ketolysis generates succinate that increases H3K4me3 at the Arg1 promoter, promoting Arg1 transcription, TAM polarization to a protumor phenotype, and CD8+ T-cell exhaustion.\",\n      \"method\": \"LysMcre-OXCT1f/f conditional knockout mice, multiplex immunohistochemistry, ChIP-seq/H3K4me3 measurement at Arg1 promoter, succinate metabolite quantification, CD8+ T-cell functional assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — macrophage-specific genetic KO with multiple mechanistic readouts (epigenetic, metabolic, immunological)\",\n      \"pmids\": [\"38759889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"After traumatic brain injury (TBI), OXCT1 expression decreases in hippocampal neurons; adeno-associated virus-mediated OXCT1 overexpression increases SIRT3 expression and reduces acetylated SOD2, thereby decreasing reactive oxygen species production in injured hippocampal neurons, reducing neuronal death, and improving cognitive function.\",\n      \"method\": \"AAV-mediated OXCT1 overexpression in mice, TBI weight-drop model, immunoblot for SIRT3 and acetyl-SOD2, DHE staining for ROS, Nissl staining for neuronal death, cognitive behavioral tests\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with defined molecular (SIRT3/SOD2) and functional (ROS, cognition) readouts; single lab\",\n      \"pmids\": [\"36921750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OXCT1 overexpression in hippocampal neurons after subarachnoid hemorrhage activates the Akt/GSK-3β/β-catenin signaling pathway to promote adult hippocampal neurogenesis; this effect is abolished by the PI3K inhibitor LY294002, placing OXCT1-dependent ketone metabolism upstream of Akt signaling in neurogenesis.\",\n      \"method\": \"AAV-mediated OXCT1 overexpression in SAH mouse model, LY294002 pharmacological inhibition, doublecortin/EdU dual staining for neurogenesis, immunofluorescence and immunoblot for Akt/GSK-3β/β-catenin, Morris water maze and Y-maze\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via pharmacological inhibitor plus gain-of-function with defined pathway and functional readout; single lab\",\n      \"pmids\": [\"38199308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OXCT1 succinylates PGK1 at K146, increasing PGK1 protein stability (reducing its ubiquitination without affecting mRNA), thereby enhancing aerobic glycolysis and PD-L1 expression to promote immune escape in triple-negative breast cancer. KMT5A methyltransferase increases H4K20me1 at the OXCT1 promoter to drive OXCT1 expression upstream.\",\n      \"method\": \"OXCT1 overexpression/knockdown in TNBC cells and patient-derived organoids, succinylation site mapping (PGK1 K146), ubiquitination assay, KMT5A ChIP for H4K20me1 at OXCT1 promoter, T-cell killing assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with succinylation site mapping and upstream epigenetic regulation; single lab\",\n      \"pmids\": [\"40634657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OXCT1 knockdown in ovine preadipocytes promotes lipid accumulation, while overexpression reduces it, demonstrating that OXCT1 negatively regulates adipogenesis/lipid deposition in adipocytes.\",\n      \"method\": \"OXCT1 siRNA knockdown and overexpression in ovine adipocytes, lipid accumulation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD/OE with phenotypic readout but no downstream pathway placement\",\n      \"pmids\": [\"30928098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OXCT1 overexpression in PDAC cells promotes gemcitabine resistance by activating the NF-κB signaling pathway; an NF-κB inhibitor reverses OXCT1-mediated gemcitabine resistance both in vitro and in mouse tumor models.\",\n      \"method\": \"OXCT1 overexpression/knockdown in PDAC cell lines, NF-κB inhibitor rescue, GSEA pathway analysis, mouse xenograft tumor models, apoptosis assay\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis (NF-κB inhibitor reversal) with in vivo validation; single lab\",\n      \"pmids\": [\"34804914\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OXCT1 encodes the mitochondrial succinyl-CoA:3-oxoacid CoA transferase (SCOT) that catalyzes the rate-limiting step of ketolysis in extrahepatic tissues; beyond this canonical role, OXCT1 also acts as a lysine succinyltransferase (requiring residue G424) that succinylates substrates such as LACTB (inhibiting its protease activity) and PGK1 (stabilizing it), and is itself activated by SUCLA2-mediated K421 succinylation downstream of IGF1/ERK2/PIN1 signaling; its protein stability is regulated by frataxin-dependent suppression of ubiquitin-proteasome degradation, its catalytic activity is inhibited by peroxynitrite-mediated nitration at Y4 and Y76, and it participates in neuronal neuroprotection via SIRT3-SOD2 and Akt/GSK-3β/β-catenin pathways, as well as in macrophage immunometabolism through succinate-driven epigenetic regulation of Arg1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OXCT1 encodes the mitochondrial succinyl-CoA:3-oxoacid CoA transferase (SCOT) that catalyzes the rate-limiting step of extrahepatic ketolysis by transferring CoA from succinyl-CoA to acetoacetate, and loss-of-function mutations cause hereditary SCOT deficiency with episodic ketoacidosis [PMID:8751852, PMID:10964512]. Beyond its canonical ketolytic activity, OXCT1 functions as a lysine succinyltransferase—dependent on residue G424—that succinylates substrates including LACTB (inhibiting its protease activity to enhance mitochondrial respiration) and PGK1 (stabilizing the protein to promote glycolysis), linking OXCT1 to hepatocellular carcinoma and breast cancer progression [PMID:38176415, PMID:40634657]. OXCT1 catalytic activity is itself regulated by SUCLA2-mediated succinylation at K421 downstream of IGF1/ERK2/PIN1 signaling, by frataxin-dependent suppression of proteasomal degradation, and by inhibitory peroxynitrite-mediated nitration at Y4 and Y76 [PMID:39862868, PMID:36016708, PMID:20527992]. In macrophages, OXCT1-driven ketolysis generates succinate that increases H3K4me3 at the Arg1 promoter to promote protumor polarization, while in neurons OXCT1 overexpression confers neuroprotection via the SIRT3-SOD2 and Akt/GSK-3β/β-catenin pathways [PMID:38759889, PMID:36921750, PMID:38199308].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing OXCT1 as the gene encoding SCOT and linking its loss to hereditary ketoacidosis answered the fundamental question of what enzyme catalyzes the rate-limiting step of ketolysis in extrahepatic tissues.\",\n      \"evidence\": \"cDNA cloning, chromosomal mapping to 5p13, and identification of homozygous S283X nonsense mutation in SCOT-deficient patient fibroblasts\",\n      \"pmids\": [\"8751852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"enzymatic mechanism and active-site architecture not yet resolved\", \"tissue-specific expression pattern not systematically characterized\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Functional expression of patient-derived missense alleles in SCOT-deficient cells established the principle that individual residues (V133, C456) are essential for catalytic activity while others (T58) are neutral, enabling genotype-phenotype correlation.\",\n      \"evidence\": \"Transient expression of V133E, C456F, and T58M mutant cDNAs in immortalized SCOT-deficient fibroblasts with activity assay\",\n      \"pmids\": [\"9671268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no crystal structure to rationalize why specific residues are essential\", \"incomplete allelic series\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Determining the full genomic structure (17 exons, >100 kb) and using homology modeling to predict dimerization and active-site residues—validated by mutagenesis—provided the first structural framework for understanding SCOT function.\",\n      \"evidence\": \"Gene cloning, homology modeling against A. fermentans glutaconate CoA transferase, transient expression of G219E, V221M, G324E mutants\",\n      \"pmids\": [\"10964512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"homology model not experimentally validated by crystallography\", \"dimerization interface not confirmed by biophysical methods\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that the T435N and later R268H mutations are temperature-sensitive explained the clinical observation that febrile illness triggers ketoacidotic crises in patients with residual SCOT activity, revealing protein stability as a disease-modifying factor.\",\n      \"evidence\": \"Transient expression at 30°C, 37°C, and 40°C with heat-treatment stability assays; 3D structural analysis of the R268-D52 salt bridge\",\n      \"pmids\": [\"15496607\", \"17706444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no in vivo confirmation of temperature sensitivity in animal models\", \"folding intermediates and chaperone dependencies not characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of Y4 and Y76 as peroxynitrite-nitration sites that causally inhibit SCOT activity in diabetic heart mitochondria established a post-translational mechanism for OXCT1 inactivation in metabolic disease.\",\n      \"evidence\": \"Recombinant SCOT treated with peroxynitrite, LC-ESI-MS/MS site identification, Y4F/Y76F mutagenesis protecting activity\",\n      \"pmids\": [\"20527992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"in vivo relevance of nitration in diabetic cardiomyopathy not directly tested\", \"whether nitration is reversible or irreversible in cells is unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"OXCT1 knockdown in beta-cells demonstrated that SCOT-dependent ketone body metabolism is required for normal glucose- and metabolite-stimulated insulin secretion, extending its role beyond simple fuel oxidation.\",\n      \"evidence\": \"shRNA knockdown in INS-1 832/13 insulinoma cells with insulin secretion assay\",\n      \"pmids\": [\"20460097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking OXCT1 to insulin granule exocytosis not defined\", \"not confirmed in primary islets or in vivo\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The crystal structure of human SCOT enabled structure-based classification of all known pathogenic alleles, resolving whether mutations affect stability, dimerization, or catalysis.\",\n      \"evidence\": \"X-ray crystallography of human SCOT with mapping of disease mutations\",\n      \"pmids\": [\"23420214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no co-crystal with substrate or CoA intermediate\", \"conformational dynamics during catalysis not captured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that frataxin physically interacts with OXCT1 and protects it from ubiquitin-proteasome degradation revealed a new layer of OXCT1 regulation and connected Friedreich's ataxia pathophysiology to impaired ketolysis.\",\n      \"evidence\": \"Reciprocal co-IP in vivo and in vitro, frataxin OE/KD across human fibroblasts and mouse models, proteasome inhibitor rescue, ketone body metabolite quantification\",\n      \"pmids\": [\"36016708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase responsible for OXCT1 degradation not identified\", \"structural basis of frataxin-OXCT1 interaction unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"OXCT1 overexpression after traumatic brain injury showed that OXCT1-dependent ketone metabolism activates the SIRT3-SOD2 axis to reduce ROS and neuronal death, positioning OXCT1 as a neuroprotective factor.\",\n      \"evidence\": \"AAV-mediated OXCT1 overexpression in mouse TBI model, immunoblot for SIRT3/acetyl-SOD2, ROS quantification, cognitive behavioral tests\",\n      \"pmids\": [\"36921750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether SIRT3 activation is a direct or indirect consequence of enhanced ketolysis is unclear\", \"loss-of-function approach not performed in this system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The revelation that OXCT1 possesses intrinsic lysine succinyltransferase activity (dependent on G424) that succinylates LACTB to inhibit its protease function fundamentally expanded the enzyme's functional repertoire beyond ketolysis.\",\n      \"evidence\": \"In vitro succinyltransferase assay, G424 mutagenesis, LACTB K284 succinylation mapping by MS and Co-IP, mitochondrial respiration measurements\",\n      \"pmids\": [\"38176415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"full substrate scope of OXCT1 succinyltransferase activity unknown\", \"structural basis for dual catalytic activities not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapping the IGF1→ERK2→SUCLA2(S124 phosphorylation)→PIN1→SUCLA2-OXCT1 interaction→K421 succinylation cascade showed how growth factor signaling activates OXCT1 ketolytic activity to fuel tumor growth.\",\n      \"evidence\": \"Co-IP of OXCT1-SUCLA2, phospho- and isomerization-deficient mutants, K421 mutagenesis, in vitro ketolysis assay, mouse tumor models\",\n      \"pmids\": [\"39862868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether K421 succinylation also affects succinyltransferase activity is untested\", \"desuccinylase(s) reversing K421 modification not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Macrophage-specific OXCT1 knockout demonstrated that OXCT1-driven succinate accumulation epigenetically activates Arg1 via H3K4me3, promoting protumor macrophage polarization and CD8+ T-cell exhaustion.\",\n      \"evidence\": \"LysMcre-OXCT1f/f conditional KO mice, ChIP-seq for H3K4me3 at Arg1 promoter, succinate metabolomics, CD8+ T-cell functional assays\",\n      \"pmids\": [\"38759889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"which histone methyltransferase is recruited by succinate accumulation not identified\", \"generalizability beyond liver cancer TAMs not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of PGK1 K146 as a second OXCT1 succinyltransferase substrate that stabilizes PGK1 protein and promotes glycolysis/PD-L1-mediated immune evasion broadened the oncogenic scope of OXCT1's non-canonical activity.\",\n      \"evidence\": \"Succinylation site mapping on PGK1, ubiquitination assay, KMT5A ChIP for H4K20me1 at OXCT1 promoter, T-cell killing assay in TNBC cells and PDOs\",\n      \"pmids\": [\"40634657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether PGK1 succinylation occurs in non-cancer contexts is unknown\", \"OXCT1 succinyltransferase activity has not been reconstituted with purified components for PGK1\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full substrate repertoire of OXCT1's succinyltransferase activity, the structural basis for its dual enzymatic functions, the identity of the E3 ligase mediating OXCT1 proteasomal turnover, and whether the non-canonical activities operate in normal physiology or are cancer-specific.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no structural model of succinyltransferase active site or dual-function mechanism\", \"E3 ubiquitin ligase for OXCT1 degradation not identified\", \"succinyltransferase substrate scope not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 3, 6, 7, 8, 14, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [14, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 4, 8, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 9, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 15, 16, 19, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14, 15, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"SCOT homodimer\"\n    ],\n    \"partners\": [\n      \"SUCLA2\",\n      \"FXN\",\n      \"LACTB\",\n      \"PGK1\",\n      \"ERK2\",\n      \"PIN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}