{"gene":"CPT2","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2024,"finding":"Sirt5 (a lysine de-succinylase) directly desuccinylates CPT2 at Lys424; succinylation of Lys424 by Sirt5 deficiency inactivates CPT2 enzymatic activity, leading to accumulation of long-chain fatty acyl-carnitines and impaired fatty acid oxidation in the diabetic heart. The CPT2 K424R mutation (mimicking desuccinylation) counteracts this inactivation.","method":"Succinylomics mass spectrometry, site-directed mutagenesis (K424R), enzymatic activity assays, cardiac-specific Sirt5 knockout and overexpression mouse models","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 — succinylomics identification + mutagenesis + enzymatic assay + in vivo genetic models, all in single study with strong mechanistic controls","pmids":["38718533"],"is_preprint":false},{"year":2019,"finding":"Low-level palmitate activates a CDK1-SIRT3-CPT2 cascade in liver cells: CDK1 phosphorylates SIRT3, which in turn deacetylates and dimerizes CPT2, thereby enhancing fatty acid oxidation and mitochondrial homeostasis.","method":"In vitro kinase assays, co-immunoprecipitation, SIRT3 phosphorylation and CPT2 acetylation/deacetylation assays, liver cell models, mouse CCl4 hepatotoxicity model","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical assays (kinase, deacetylase, dimerization) plus in vivo validation","pmids":["31866205"],"is_preprint":false},{"year":2025,"finding":"SIRT2, localized in cardiac mitochondria, deacetylates CPT2 at K239, which enhances CPT2 ubiquitination and reduces protein stability, thereby inhibiting fatty acid oxidation and ROS production in the diabetic heart.","method":"Cardiac-specific SIRT2 overexpression/knockdown mouse models (STZ/HFD), co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis at K239, FAO measurement","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo genetic models combined with biochemical identification of modification site and functional consequences","pmids":["39781464"],"is_preprint":false},{"year":2020,"finding":"HRD1 (an E3 ubiquitin ligase) directly ubiquitinates CPT2 via K48-linked ubiquitination, paradoxically stabilizing CPT2 protein; under glutamine deprivation, HRD1 downregulation leads to CPT2 destabilization and impaired fatty acid oxidation in triple-negative breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays, HRD1 knockdown/knockout, CPT2 inhibition, in vitro and in vivo proliferation assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and ubiquitination assay with functional follow-up, single lab","pmids":["33207079"],"is_preprint":false},{"year":2025,"finding":"SLC44A2 (a mitochondrial membrane protein) promotes MUL1 (mitochondrial E3 ubiquitin ligase)-mediated degradation of CPT2 by enhancing the MUL1-CPT2 protein interaction, thereby suppressing fatty acid oxidation and colorectal cancer progression.","method":"Co-immunoprecipitation, ubiquitination assays, SLC44A2 overexpression/knockdown, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP showing protein interaction and downstream functional consequence, single lab","pmids":["40592838"],"is_preprint":false},{"year":2022,"finding":"CPT2 K79 acetylation (driven by NAD+ exhaustion and decreased Sirt3 activity during platelet storage) attenuates CPT2-dependent fatty acid oxidation, causing long-chain acylcarnitine accumulation, mitochondrial damage, and shortened platelet life span.","method":"Acetylation site identification by mass spectrometry, Sirt3 activity assays, pharmacological Sirt3 agonists, CPT1/AMPK inhibitors, in vitro and in vivo platelet survival assays","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 — MS-identified modification site with functional pharmacological validation in vitro and in vivo, single lab","pmids":["35728063"],"is_preprint":false},{"year":1990,"finding":"CPT2 (carnitine palmitoyltransferase from the mitochondrial inner membrane) is intrinsically insensitive to malonyl-CoA inhibition; however, when reconstituted with a malonyl-CoA binding protein solubilized from the outer membrane, CPT2 becomes inhibitable by malonyl-CoA, demonstrating that malonyl-CoA sensitivity requires the outer membrane component.","method":"Biochemical fractionation of rat liver mitochondrial inner and outer membranes, cholate extraction, CPT activity reconstitution assay, [14C]malonyl-CoA binding","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution experiment directly demonstrating the mechanism of malonyl-CoA sensitivity","pmids":["2401367"],"is_preprint":false},{"year":1989,"finding":"CPT1 and CPT2 are distinct enzymes: patients with hepatic CPT1 deficiency in fibroblasts and liver show normal CPT1 and CPT2 activities in muscle under saturating substrate conditions, while muscular-form patients show marked CPT2 deficiency. This establishes that CPT1 and CPT2 are separate proteins and that CPT1 may exist as tissue-specific isoforms.","method":"Isotope exchange assay differentiating CPT1 and CPT2 activities in muscle biopsies; kinetic analysis (Km for carnitine and palmitoyl-CoA) in patient and control samples","journal":"Journal of the neurological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — direct enzymatic assay in patient tissues distinguishing CPT1 from CPT2, but single lab and limited patient numbers","pmids":["2809620"],"is_preprint":false},{"year":1998,"finding":"Two missense mutations in CPT2 (E174K and F383Y) markedly decrease CPT2 catalytic activity; a polymorphism F352C does not alter activity. Genotype-phenotype analysis shows F383Y (homozygous) causes hepatic phenotype and E174K (homozygous) causes muscular phenotype of CPT II deficiency.","method":"Transfection of mutant CPT2 cDNA in COS-1 cells, enzymatic activity assay, molecular analysis","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution by cell transfection with direct enzymatic activity measurement and structure-function conclusions","pmids":["9600456"],"is_preprint":false},{"year":2022,"finding":"CPT2 mediates fatty acid oxidation in the mitochondria; its inhibition by aminocarnitine during endotoxaemia causes accumulation of long-chain acylcarnitines in the heart, which inhibits pyruvate metabolism and exacerbates inflammation-induced cardiac dysfunction.","method":"LPS-induced endotoxaemia mouse model, aminocarnitine pharmacological CPT2 inhibition, mitochondrial respirometry, acylcarnitine metabolite profiling","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with metabolite profiling and functional cardiac readout, single lab","pmids":["32896106"],"is_preprint":false},{"year":2021,"finding":"E2F2 binds directly to the CPT2 promoter and represses its transcription in mouse liver during high-fat diet/DEN-induced hepatocarcinogenesis; E2f1 and E2f2 knockout mice show enhanced CPT2 expression and increased fatty acid oxidation, and are resistant to hepatocarcinogenesis.","method":"ChIP showing E2F2 binding to Cpt2 promoter, E2f1/E2f2 knockout mouse models, E2f2 liver-specific knockdown and overexpression, FAO measurement, gene expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP for direct promoter binding, multiple genetic loss-of-function models with defined FAO phenotype","pmids":["33771899"],"is_preprint":false},{"year":2022,"finding":"The FAM3A-ATP-P2 receptor-calmodulin (CaM)-FOXA2-CPT2 pathway regulates fatty acid oxidation in hepatocytes: FAM3A-induced ATP release activates P2 receptors, promoting CaM nuclear translocation where it acts as a co-activator of FOXA2 to drive CPT2 transcription.","method":"High-throughput RNA sequencing, CaM nuclear translocation assays, FOXA2 co-activator assays, FAM3A-deficient hepatocytes and mice, pharmacological pathway dissection","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic steps validated in both cell and mouse genetic models, single lab","pmids":["35995281"],"is_preprint":false},{"year":2025,"finding":"SLC25A42 (a mitochondrial CoA transporter) promotes acetylation of CPT2, which increases CPT2 expression and enhances fatty acid oxidation; this reprograms lipid metabolism to support gastric cancer growth and ferroptosis resistance.","method":"Co-immunoprecipitation, acetylation assays, SLC25A42 knockout/overexpression, FAO measurement, in vitro and in vivo proliferation and ferroptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — biochemical acetylation assay linked to functional metabolic and proliferation readouts, single lab","pmids":["40246810"],"is_preprint":false},{"year":2024,"finding":"CPT2-mediated fatty acid oxidation is dispensable for humoral immunity: lymphocyte-specific CPT2 knockout mice show markedly reduced fatty acid-derived citrate production in B cells (confirmed by stable [13C] isotope tracing) but exhibit normal B cell development, activation, germinal center formation, and antibody production.","method":"Lymphocyte-specific CPT2 knockout mice, stable [13C] isotope tracing of fatty acid oxidation, flow cytometry, in vivo antigen challenge","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — isotope tracing confirming metabolic block, combined with rigorous in vivo genetic model and functional immunological readouts","pmids":["39258879"],"is_preprint":false},{"year":2018,"finding":"AMPK activation by GSK773 upregulates CPT2 protein expression in patient-derived CPT2-deficient myotubes, correcting deficient FAO flux and C16-acylcarnitine accumulation; effects are mediated through PGC-1α, ROS, and p38 MAPK pathways.","method":"Patient-derived myotube cultures, FAO flux assays, acylcarnitine profiling, siRNA knockdowns, pharmacological inhibitors, CPT2 protein quantification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in patient-derived cells with defined mechanistic pathway, single lab","pmids":["30007356"],"is_preprint":false},{"year":2025,"finding":"CPT2 knockdown in colorectal cancer cells causes accumulation of glycerophospholipids (phosphatidylcholine and phosphatidylethanolamine) via enhanced GPAT4-mediated glycerophospholipid biosynthesis; this promotes autophagosome maturation/elongation and selective autophagy (lipophagy), accelerating tumor progression.","method":"CPT2 knockdown, metabolite profiling (glycerophospholipids), transcriptomics, GPAT4 functional analysis, autophagy flux assays, in vitro and in vivo models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — metabolite profiling plus transcriptomic and functional autophagy validation, single lab","pmids":["41107458"],"is_preprint":false},{"year":2024,"finding":"GBA3 acts as a transcriptional co-activator to promote CPT2 expression in hepatocytes, thereby increasing fatty acid oxidation, reducing ROS, inhibiting MLKL-mediated necroptosis, and slowing NAFLD progression.","method":"GBA3 overexpression in HepG2 cells and rat NAFLD model, Seahorse metabolic assay, western blotting, immunohistochemistry, flow cytometry for ROS and apoptosis","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic link between transcriptional co-activation and FAO with metabolic readouts, single lab","pmids":["38428407"],"is_preprint":false}],"current_model":"CPT2 is a mitochondrial inner membrane enzyme that catalyzes the reconversion of long-chain fatty acyl-carnitines to fatty acyl-CoA for beta-oxidation; its activity is intrinsically malonyl-CoA insensitive but becomes inhibitable when reconstituted with the outer membrane malonyl-CoA binding protein, and is regulated by multiple post-translational modifications including Sirt5-mediated desuccinylation at Lys424 (activating), SIRT2-mediated deacetylation at Lys239 (promoting ubiquitin-dependent degradation), and Sirt3-dependent deacetylation/dimerization (activating), while its transcription is directly repressed by E2F2 and induced by FOXA2 downstream of FAM3A-CaM signaling, collectively placing CPT2 as a central, multiply-regulated gateway controlling mitochondrial fatty acid oxidation in heart, liver, muscle, and immune cells."},"narrative":{"teleology":[{"year":1989,"claim":"Establishing that CPT1 and CPT2 are distinct gene products — enzymatic assays in patients with tissue-specific CPT deficiency demonstrated that CPT2 is a separate enzyme from CPT1, resolving a long-standing question about whether carnitine palmitoyltransferase activity arose from one or two genes.","evidence":"Isotope exchange assays differentiating CPT1 and CPT2 kinetics in muscle and liver biopsies from deficient patients","pmids":["2809620"],"confidence":"Medium","gaps":["Limited patient numbers from single lab","Tissue-specific isoform identity of CPT1 not molecularly resolved in this study"]},{"year":1990,"claim":"Determining the basis of malonyl-CoA regulation — reconstitution of purified inner-membrane CPT2 with an outer-membrane malonyl-CoA-binding protein showed that CPT2 itself is malonyl-CoA insensitive and that inhibition requires an outer-membrane component, establishing the two-component model of carnitine shuttle regulation.","evidence":"Biochemical fractionation, cholate extraction, and reconstitution of rat liver mitochondrial membranes with [¹⁴C]malonyl-CoA binding assays","pmids":["2401367"],"confidence":"High","gaps":["Identity of the outer-membrane malonyl-CoA binding protein not molecularly cloned","Whether reconstituted regulation is physiologically relevant in intact mitochondria not tested"]},{"year":1998,"claim":"Linking specific mutations to CPT II deficiency phenotypes — expression of E174K and F383Y mutants in COS-1 cells showed that each markedly reduces catalytic activity, with genotype–phenotype correlation to muscular versus hepatic disease forms, establishing the molecular basis of CPT II deficiency.","evidence":"Transfection of mutant CPT2 cDNA in COS-1 cells with direct enzymatic activity measurement","pmids":["9600456"],"confidence":"High","gaps":["Structural mechanism by which each mutation impairs catalysis unknown","No crystal structure available to explain residue-specific effects"]},{"year":2018,"claim":"Identifying a pharmacological rescue pathway for CPT2 deficiency — AMPK activation by GSK773 upregulated CPT2 protein via PGC-1α/ROS/p38 MAPK in patient-derived myotubes, correcting fatty acid oxidation flux, showing CPT2 expression is amenable to transcriptional/signaling rescue.","evidence":"Patient-derived CPT2-deficient myotubes treated with AMPK agonist, FAO flux assays, siRNA epistasis","pmids":["30007356"],"confidence":"Medium","gaps":["In vivo efficacy of AMPK-mediated CPT2 rescue not demonstrated","Whether residual mutant CPT2 protein is stabilized or new wild-type-like protein is induced unclear"]},{"year":2019,"claim":"Revealing a deacetylation–dimerization activation axis — low-level palmitate triggers a CDK1→SIRT3 cascade that deacetylates and dimerizes CPT2, enhancing fatty acid oxidation, establishing that CPT2 quaternary structure is regulated by acetylation status.","evidence":"In vitro kinase assays, co-IP, SIRT3 phosphorylation and CPT2 acetylation/dimerization assays in liver cells and mouse CCl4 model","pmids":["31866205"],"confidence":"High","gaps":["Specific acetylation sites on CPT2 targeted by SIRT3 in this cascade not mapped","Structural basis of how dimerization enhances activity unknown"]},{"year":2020,"claim":"Uncovering a stabilizing ubiquitination mechanism — HRD1-mediated K48-linked ubiquitination paradoxically stabilizes CPT2 rather than promoting degradation, and its loss under glutamine deprivation destabilizes CPT2 in breast cancer cells, revealing a non-canonical ubiquitin signal.","evidence":"Reciprocal co-IP, ubiquitination assays, HRD1 knockdown/knockout in triple-negative breast cancer cells","pmids":["33207079"],"confidence":"Medium","gaps":["Mechanism by which K48-ubiquitin stabilizes rather than degrades CPT2 unresolved","Not validated outside breast cancer cell lines"]},{"year":2021,"claim":"Identifying direct transcriptional repression of CPT2 — ChIP demonstrated E2F2 binds the CPT2 promoter to repress transcription; E2f1/E2f2 knockout mice showed elevated CPT2, increased FAO, and resistance to hepatocarcinogenesis, linking CPT2 transcription to cell-cycle regulators and cancer.","evidence":"ChIP for E2F2 on Cpt2 promoter, E2f1/E2f2 knockout mice, liver-specific knockdown/overexpression, FAO assays","pmids":["33771899"],"confidence":"High","gaps":["Whether E2F2 repression is cell-cycle-phase dependent unknown","Other E2F family members' roles at the CPT2 promoter not systematically tested"]},{"year":2022,"claim":"Defining an upstream signaling cascade for CPT2 induction — FAM3A-released ATP activates P2 receptors, driving CaM nuclear translocation where CaM co-activates FOXA2 to transcribe CPT2 in hepatocytes, establishing a complete extracellular-to-nuclear signaling pathway for CPT2 regulation.","evidence":"RNA-seq, CaM nuclear translocation assays, FOXA2 co-activator assays, FAM3A-deficient hepatocytes and mice","pmids":["35995281"],"confidence":"Medium","gaps":["Whether FOXA2 directly binds CPT2 promoter elements not shown by ChIP","Single-lab observation awaiting replication"]},{"year":2022,"claim":"Mapping a Sirt3-dependent acetylation site controlling platelet survival — K79 acetylation of CPT2 (accumulating as NAD⁺/Sirt3 activity declines during storage) attenuates fatty acid oxidation, causing acylcarnitine buildup and shortened platelet lifespan, connecting CPT2 post-translational regulation to transfusion biology.","evidence":"Mass spectrometry acetylation site identification, Sirt3 activity assays, pharmacological agonists, in vitro/in vivo platelet survival assays","pmids":["35728063"],"confidence":"Medium","gaps":["K79 mutagenesis not performed to confirm site specificity","Role of other deacetylases at this site not excluded"]},{"year":2024,"claim":"Identifying succinylation as a novel inhibitory modification — Sirt5-mediated desuccinylation at Lys424 activates CPT2; loss of Sirt5 in diabetic hearts causes Lys424 succinylation, inactivating CPT2 and impairing FAO, adding a new post-translational regulatory dimension.","evidence":"Succinylomics MS, K424R mutagenesis, enzymatic activity assays, cardiac-specific Sirt5 knockout and overexpression mice","pmids":["38718533"],"confidence":"High","gaps":["Succinyl-CoA-dependent succinylation writer not identified","Whether Lys424 succinylation occurs in non-cardiac tissues unknown"]},{"year":2024,"claim":"Demonstrating that CPT2-dependent FAO is dispensable for humoral immunity — lymphocyte-specific CPT2 knockout mice showed markedly reduced fatty acid-derived citrate in B cells yet normal B cell development, germinal center reactions, and antibody production, delimiting the tissues in which CPT2 is functionally essential.","evidence":"Lymphocyte-specific CPT2 knockout mice, ¹³C isotope tracing, flow cytometry, in vivo antigen challenge","pmids":["39258879"],"confidence":"High","gaps":["Whether CPT2-independent compensatory FAO pathways exist in B cells not investigated","T cell-specific functional consequences not deeply characterized"]},{"year":2025,"claim":"Revealing a degradation-promoting deacetylation — SIRT2 deacetylates CPT2 at Lys239, promoting ubiquitination and degradation, thereby suppressing FAO in the diabetic heart — in contrast to SIRT3-mediated deacetylation which activates CPT2, demonstrating sirtuin-specific opposing outcomes.","evidence":"Cardiac-specific SIRT2 overexpression/knockdown in STZ/HFD diabetic mice, K239 mutagenesis, ubiquitination assays","pmids":["39781464"],"confidence":"High","gaps":["The E3 ligase mediating SIRT2-induced CPT2 ubiquitination not identified","How K239 deacetylation exposes a degron is structurally unexplained"]},{"year":null,"claim":"A high-resolution structure of CPT2 — ideally with bound substrate or acyl-carnitine — is needed to explain how specific lysine modifications (K79, K239, K424) and disease mutations (E174K, F383Y) affect catalysis and dimerization, and how the outer-membrane malonyl-CoA-binding protein confers inhibitor sensitivity.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of mammalian CPT2 published","Molecular identity of the outer-membrane malonyl-CoA-binding partner remains unresolved","Relative contributions of competing sirtuin pathways in vivo across tissues not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,6,7,8,9]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,5,6,7,9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2,5,6,9,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,14]}],"complexes":[],"partners":["SIRT3","SIRT2","SIRT5","HRD1","MUL1","E2F2","FOXA2","CDK1"],"other_free_text":[]},"mechanistic_narrative":"CPT2 is a mitochondrial inner membrane acyltransferase that converts long-chain fatty acyl-carnitines back to fatty acyl-CoA, constituting the terminal step of the carnitine shuttle and a critical gateway for mitochondrial fatty acid β-oxidation in heart, liver, muscle, and immune cells. CPT2 is intrinsically insensitive to malonyl-CoA but acquires malonyl-CoA inhibition when reconstituted with an outer-membrane malonyl-CoA-binding protein [PMID:2401367], and its catalytic activity is regulated by multiple post-translational modifications: Sirt5-mediated desuccinylation at Lys424 and Sirt3-mediated deacetylation activate CPT2 [PMID:38718533, PMID:31866205], whereas SIRT2-mediated deacetylation at Lys239 promotes K48-linked ubiquitination and degradation [PMID:39781464], and HRD1-mediated ubiquitination paradoxically stabilizes the protein [PMID:33207079]. At the transcriptional level, CPT2 expression is repressed by E2F2 binding to its promoter and induced by the FAM3A–CaM–FOXA2 signaling axis [PMID:33771899, PMID:35995281]. Loss-of-function mutations such as E174K and F383Y cause the muscular and hepatic forms of CPT II deficiency, respectively [PMID:9600456]."},"prefetch_data":{"uniprot":{"accession":"P23786","full_name":"Carnitine O-palmitoyltransferase 2, mitochondrial","aliases":["Carnitine palmitoyltransferase II","CPT II"],"length_aa":658,"mass_kda":73.8,"function":"Involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl-CoA metabolites (PubMed:20538056, PubMed:24780397). Reconverts acylcarnitines back into the respective acyl-CoA esters that can then undergo beta-oxidation, an essential step for the mitochondrial uptake of long-chain fatty acids and their subsequent beta-oxidation in the mitochondrion. Active with medium (C8-C12) and long-chain (C14-C18) acyl-CoA esters (PubMed:20538056)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P23786/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPT2","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CPT2","total_profiled":1310},"omim":[{"mim_id":"614480","title":"HYPERTRIGLYCERIDEMIA, TRANSIENT INFANTILE; HTGTI","url":"https://www.omim.org/entry/614480"},{"mim_id":"614212","title":"ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED, SUSCEPTIBILITY TO, 4; IIAE4","url":"https://www.omim.org/entry/614212"},{"mim_id":"610551","title":"ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED (HERPES-SPECIFIC), SUSCEPTIBILITY TO, 1; IIAE1","url":"https://www.omim.org/entry/610551"},{"mim_id":"609016","title":"LONG-CHAIN 3-HYDROXYACYL-CoA DEHYDROGENASE DEFICIENCY","url":"https://www.omim.org/entry/609016"},{"mim_id":"608836","title":"CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL","url":"https://www.omim.org/entry/608836"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":85.2}],"url":"https://www.proteinatlas.org/search/CPT2"},"hgnc":{"alias_symbol":["CPTASE"],"prev_symbol":["CPT1"]},"alphafold":{"accession":"P23786","domains":[{"cath_id":"3.30.559.70","chopping":"130-168_217-438","consensus_level":"high","plddt":97.6689,"start":130,"end":438},{"cath_id":"3.30.559.10","chopping":"441-651","consensus_level":"high","plddt":97.203,"start":441,"end":651}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23786","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23786-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23786-F1-predicted_aligned_error_v6.png","plddt_mean":94.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPT2","jax_strain_url":"https://www.jax.org/strain/search?query=CPT2"},"sequence":{"accession":"P23786","fasta_url":"https://rest.uniprot.org/uniprotkb/P23786.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23786/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23786"}},"corpus_meta":[{"pmid":"29891721","id":"PMC_29891721","title":"Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29891721","citation_count":276,"is_preprint":false},{"pmid":"25122071","id":"PMC_25122071","title":"Lipid catabolism via CPT1 as a therapeutic target for prostate cancer.","date":"2014","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/25122071","citation_count":257,"is_preprint":false},{"pmid":"36917141","id":"PMC_36917141","title":"Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/36917141","citation_count":145,"is_preprint":false},{"pmid":"15199055","id":"PMC_15199055","title":"RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15199055","citation_count":144,"is_preprint":false},{"pmid":"22938691","id":"PMC_22938691","title":"Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake.","date":"2012","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/22938691","citation_count":81,"is_preprint":false},{"pmid":"3029130","id":"PMC_3029130","title":"Mutants of Saccharomyces cerevisiae defective in sn-1,2-diacylglycerol cholinephosphotransferase. 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investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36990664","citation_count":4,"is_preprint":false},{"pmid":"27868312","id":"PMC_27868312","title":"Effect of chicken leptin recptor short hairpin RNA on expression of JAK2, STAT3, SOCS3 and CPT1 genes in chicken preadipocytes.","date":"2016","source":"Animal science journal = Nihon chikusan Gakkaiho","url":"https://pubmed.ncbi.nlm.nih.gov/27868312","citation_count":4,"is_preprint":false},{"pmid":"41274422","id":"PMC_41274422","title":"Rewiring lipid Metabolism: The central role of CPT1 in metabolic dysfunction.","date":"2025","source":"Progress in biophysics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41274422","citation_count":3,"is_preprint":false},{"pmid":"41107458","id":"PMC_41107458","title":"CPT2 inhibition enhances selective autophagy and proliferation in colorectal cancer via GPAT4-dependent glycerophospholipid biosynthesis.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41107458","citation_count":3,"is_preprint":false},{"pmid":"40348308","id":"PMC_40348308","title":"Mechanisms of Inonotus obliquus (Fr.) Pilát polysaccharides in ameliorating lipid-induced skeletal muscle insulin resistance via PI3K/AKT and AMPK/ACC1/CPT1 signaling pathways.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40348308","citation_count":3,"is_preprint":false},{"pmid":"41074134","id":"PMC_41074134","title":"Porphyromonas gingivalis extracellular vesicles exacerbated osteoporosis by disrupting osteoblast mitochondrial dynamics and inhibiting Cpt2-regulated fatty acid oxidation.","date":"2025","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41074134","citation_count":3,"is_preprint":false},{"pmid":"39834803","id":"PMC_39834803","title":"CPT1 deficiency blocks autophagic flux to promote lipid accumulation induced by co-exposure to polystyrene microplastic and cadmium.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39834803","citation_count":3,"is_preprint":false},{"pmid":"38597829","id":"PMC_38597829","title":"Inhibition of Crif1 protects fatty acid-induced POMC neuron-like cell-line damage by increasing CPT-1 function.","date":"2024","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38597829","citation_count":3,"is_preprint":false},{"pmid":"39429887","id":"PMC_39429887","title":"Recurrent rhabdomyolysis caused by palmitoyltransferase II (CPT-2) deficiency but complete normal acylcarnitine profile: A patient presentation and review of the literature.","date":"2024","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/39429887","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52333,"output_tokens":4145,"usd":0.109587},"stage2":{"model":"claude-opus-4-6","input_tokens":7581,"output_tokens":3357,"usd":0.182745},"total_usd":0.292332,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"Sirt5 (a lysine de-succinylase) directly desuccinylates CPT2 at Lys424; succinylation of Lys424 by Sirt5 deficiency inactivates CPT2 enzymatic activity, leading to accumulation of long-chain fatty acyl-carnitines and impaired fatty acid oxidation in the diabetic heart. The CPT2 K424R mutation (mimicking desuccinylation) counteracts this inactivation.\",\n      \"method\": \"Succinylomics mass spectrometry, site-directed mutagenesis (K424R), enzymatic activity assays, cardiac-specific Sirt5 knockout and overexpression mouse models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — succinylomics identification + mutagenesis + enzymatic assay + in vivo genetic models, all in single study with strong mechanistic controls\",\n      \"pmids\": [\"38718533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Low-level palmitate activates a CDK1-SIRT3-CPT2 cascade in liver cells: CDK1 phosphorylates SIRT3, which in turn deacetylates and dimerizes CPT2, thereby enhancing fatty acid oxidation and mitochondrial homeostasis.\",\n      \"method\": \"In vitro kinase assays, co-immunoprecipitation, SIRT3 phosphorylation and CPT2 acetylation/deacetylation assays, liver cell models, mouse CCl4 hepatotoxicity model\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical assays (kinase, deacetylase, dimerization) plus in vivo validation\",\n      \"pmids\": [\"31866205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRT2, localized in cardiac mitochondria, deacetylates CPT2 at K239, which enhances CPT2 ubiquitination and reduces protein stability, thereby inhibiting fatty acid oxidation and ROS production in the diabetic heart.\",\n      \"method\": \"Cardiac-specific SIRT2 overexpression/knockdown mouse models (STZ/HFD), co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis at K239, FAO measurement\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo genetic models combined with biochemical identification of modification site and functional consequences\",\n      \"pmids\": [\"39781464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HRD1 (an E3 ubiquitin ligase) directly ubiquitinates CPT2 via K48-linked ubiquitination, paradoxically stabilizing CPT2 protein; under glutamine deprivation, HRD1 downregulation leads to CPT2 destabilization and impaired fatty acid oxidation in triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, HRD1 knockdown/knockout, CPT2 inhibition, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and ubiquitination assay with functional follow-up, single lab\",\n      \"pmids\": [\"33207079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC44A2 (a mitochondrial membrane protein) promotes MUL1 (mitochondrial E3 ubiquitin ligase)-mediated degradation of CPT2 by enhancing the MUL1-CPT2 protein interaction, thereby suppressing fatty acid oxidation and colorectal cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, SLC44A2 overexpression/knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP showing protein interaction and downstream functional consequence, single lab\",\n      \"pmids\": [\"40592838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPT2 K79 acetylation (driven by NAD+ exhaustion and decreased Sirt3 activity during platelet storage) attenuates CPT2-dependent fatty acid oxidation, causing long-chain acylcarnitine accumulation, mitochondrial damage, and shortened platelet life span.\",\n      \"method\": \"Acetylation site identification by mass spectrometry, Sirt3 activity assays, pharmacological Sirt3 agonists, CPT1/AMPK inhibitors, in vitro and in vivo platelet survival assays\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified modification site with functional pharmacological validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"35728063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CPT2 (carnitine palmitoyltransferase from the mitochondrial inner membrane) is intrinsically insensitive to malonyl-CoA inhibition; however, when reconstituted with a malonyl-CoA binding protein solubilized from the outer membrane, CPT2 becomes inhibitable by malonyl-CoA, demonstrating that malonyl-CoA sensitivity requires the outer membrane component.\",\n      \"method\": \"Biochemical fractionation of rat liver mitochondrial inner and outer membranes, cholate extraction, CPT activity reconstitution assay, [14C]malonyl-CoA binding\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution experiment directly demonstrating the mechanism of malonyl-CoA sensitivity\",\n      \"pmids\": [\"2401367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CPT1 and CPT2 are distinct enzymes: patients with hepatic CPT1 deficiency in fibroblasts and liver show normal CPT1 and CPT2 activities in muscle under saturating substrate conditions, while muscular-form patients show marked CPT2 deficiency. This establishes that CPT1 and CPT2 are separate proteins and that CPT1 may exist as tissue-specific isoforms.\",\n      \"method\": \"Isotope exchange assay differentiating CPT1 and CPT2 activities in muscle biopsies; kinetic analysis (Km for carnitine and palmitoyl-CoA) in patient and control samples\",\n      \"journal\": \"Journal of the neurological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct enzymatic assay in patient tissues distinguishing CPT1 from CPT2, but single lab and limited patient numbers\",\n      \"pmids\": [\"2809620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Two missense mutations in CPT2 (E174K and F383Y) markedly decrease CPT2 catalytic activity; a polymorphism F352C does not alter activity. Genotype-phenotype analysis shows F383Y (homozygous) causes hepatic phenotype and E174K (homozygous) causes muscular phenotype of CPT II deficiency.\",\n      \"method\": \"Transfection of mutant CPT2 cDNA in COS-1 cells, enzymatic activity assay, molecular analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution by cell transfection with direct enzymatic activity measurement and structure-function conclusions\",\n      \"pmids\": [\"9600456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPT2 mediates fatty acid oxidation in the mitochondria; its inhibition by aminocarnitine during endotoxaemia causes accumulation of long-chain acylcarnitines in the heart, which inhibits pyruvate metabolism and exacerbates inflammation-induced cardiac dysfunction.\",\n      \"method\": \"LPS-induced endotoxaemia mouse model, aminocarnitine pharmacological CPT2 inhibition, mitochondrial respirometry, acylcarnitine metabolite profiling\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with metabolite profiling and functional cardiac readout, single lab\",\n      \"pmids\": [\"32896106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"E2F2 binds directly to the CPT2 promoter and represses its transcription in mouse liver during high-fat diet/DEN-induced hepatocarcinogenesis; E2f1 and E2f2 knockout mice show enhanced CPT2 expression and increased fatty acid oxidation, and are resistant to hepatocarcinogenesis.\",\n      \"method\": \"ChIP showing E2F2 binding to Cpt2 promoter, E2f1/E2f2 knockout mouse models, E2f2 liver-specific knockdown and overexpression, FAO measurement, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP for direct promoter binding, multiple genetic loss-of-function models with defined FAO phenotype\",\n      \"pmids\": [\"33771899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The FAM3A-ATP-P2 receptor-calmodulin (CaM)-FOXA2-CPT2 pathway regulates fatty acid oxidation in hepatocytes: FAM3A-induced ATP release activates P2 receptors, promoting CaM nuclear translocation where it acts as a co-activator of FOXA2 to drive CPT2 transcription.\",\n      \"method\": \"High-throughput RNA sequencing, CaM nuclear translocation assays, FOXA2 co-activator assays, FAM3A-deficient hepatocytes and mice, pharmacological pathway dissection\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic steps validated in both cell and mouse genetic models, single lab\",\n      \"pmids\": [\"35995281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC25A42 (a mitochondrial CoA transporter) promotes acetylation of CPT2, which increases CPT2 expression and enhances fatty acid oxidation; this reprograms lipid metabolism to support gastric cancer growth and ferroptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assays, SLC25A42 knockout/overexpression, FAO measurement, in vitro and in vivo proliferation and ferroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — biochemical acetylation assay linked to functional metabolic and proliferation readouts, single lab\",\n      \"pmids\": [\"40246810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPT2-mediated fatty acid oxidation is dispensable for humoral immunity: lymphocyte-specific CPT2 knockout mice show markedly reduced fatty acid-derived citrate production in B cells (confirmed by stable [13C] isotope tracing) but exhibit normal B cell development, activation, germinal center formation, and antibody production.\",\n      \"method\": \"Lymphocyte-specific CPT2 knockout mice, stable [13C] isotope tracing of fatty acid oxidation, flow cytometry, in vivo antigen challenge\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — isotope tracing confirming metabolic block, combined with rigorous in vivo genetic model and functional immunological readouts\",\n      \"pmids\": [\"39258879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AMPK activation by GSK773 upregulates CPT2 protein expression in patient-derived CPT2-deficient myotubes, correcting deficient FAO flux and C16-acylcarnitine accumulation; effects are mediated through PGC-1α, ROS, and p38 MAPK pathways.\",\n      \"method\": \"Patient-derived myotube cultures, FAO flux assays, acylcarnitine profiling, siRNA knockdowns, pharmacological inhibitors, CPT2 protein quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in patient-derived cells with defined mechanistic pathway, single lab\",\n      \"pmids\": [\"30007356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CPT2 knockdown in colorectal cancer cells causes accumulation of glycerophospholipids (phosphatidylcholine and phosphatidylethanolamine) via enhanced GPAT4-mediated glycerophospholipid biosynthesis; this promotes autophagosome maturation/elongation and selective autophagy (lipophagy), accelerating tumor progression.\",\n      \"method\": \"CPT2 knockdown, metabolite profiling (glycerophospholipids), transcriptomics, GPAT4 functional analysis, autophagy flux assays, in vitro and in vivo models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — metabolite profiling plus transcriptomic and functional autophagy validation, single lab\",\n      \"pmids\": [\"41107458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GBA3 acts as a transcriptional co-activator to promote CPT2 expression in hepatocytes, thereby increasing fatty acid oxidation, reducing ROS, inhibiting MLKL-mediated necroptosis, and slowing NAFLD progression.\",\n      \"method\": \"GBA3 overexpression in HepG2 cells and rat NAFLD model, Seahorse metabolic assay, western blotting, immunohistochemistry, flow cytometry for ROS and apoptosis\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic link between transcriptional co-activation and FAO with metabolic readouts, single lab\",\n      \"pmids\": [\"38428407\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPT2 is a mitochondrial inner membrane enzyme that catalyzes the reconversion of long-chain fatty acyl-carnitines to fatty acyl-CoA for beta-oxidation; its activity is intrinsically malonyl-CoA insensitive but becomes inhibitable when reconstituted with the outer membrane malonyl-CoA binding protein, and is regulated by multiple post-translational modifications including Sirt5-mediated desuccinylation at Lys424 (activating), SIRT2-mediated deacetylation at Lys239 (promoting ubiquitin-dependent degradation), and Sirt3-dependent deacetylation/dimerization (activating), while its transcription is directly repressed by E2F2 and induced by FOXA2 downstream of FAM3A-CaM signaling, collectively placing CPT2 as a central, multiply-regulated gateway controlling mitochondrial fatty acid oxidation in heart, liver, muscle, and immune cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CPT2 is a mitochondrial inner membrane acyltransferase that converts long-chain fatty acyl-carnitines back to fatty acyl-CoA, constituting the terminal step of the carnitine shuttle and a critical gateway for mitochondrial fatty acid β-oxidation in heart, liver, muscle, and immune cells. CPT2 is intrinsically insensitive to malonyl-CoA but acquires malonyl-CoA inhibition when reconstituted with an outer-membrane malonyl-CoA-binding protein [PMID:2401367], and its catalytic activity is regulated by multiple post-translational modifications: Sirt5-mediated desuccinylation at Lys424 and Sirt3-mediated deacetylation activate CPT2 [PMID:38718533, PMID:31866205], whereas SIRT2-mediated deacetylation at Lys239 promotes K48-linked ubiquitination and degradation [PMID:39781464], and HRD1-mediated ubiquitination paradoxically stabilizes the protein [PMID:33207079]. At the transcriptional level, CPT2 expression is repressed by E2F2 binding to its promoter and induced by the FAM3A–CaM–FOXA2 signaling axis [PMID:33771899, PMID:35995281]. Loss-of-function mutations such as E174K and F383Y cause the muscular and hepatic forms of CPT II deficiency, respectively [PMID:9600456].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing that CPT1 and CPT2 are distinct gene products — enzymatic assays in patients with tissue-specific CPT deficiency demonstrated that CPT2 is a separate enzyme from CPT1, resolving a long-standing question about whether carnitine palmitoyltransferase activity arose from one or two genes.\",\n      \"evidence\": \"Isotope exchange assays differentiating CPT1 and CPT2 kinetics in muscle and liver biopsies from deficient patients\",\n      \"pmids\": [\"2809620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited patient numbers from single lab\", \"Tissue-specific isoform identity of CPT1 not molecularly resolved in this study\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Determining the basis of malonyl-CoA regulation — reconstitution of purified inner-membrane CPT2 with an outer-membrane malonyl-CoA-binding protein showed that CPT2 itself is malonyl-CoA insensitive and that inhibition requires an outer-membrane component, establishing the two-component model of carnitine shuttle regulation.\",\n      \"evidence\": \"Biochemical fractionation, cholate extraction, and reconstitution of rat liver mitochondrial membranes with [¹⁴C]malonyl-CoA binding assays\",\n      \"pmids\": [\"2401367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the outer-membrane malonyl-CoA binding protein not molecularly cloned\", \"Whether reconstituted regulation is physiologically relevant in intact mitochondria not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linking specific mutations to CPT II deficiency phenotypes — expression of E174K and F383Y mutants in COS-1 cells showed that each markedly reduces catalytic activity, with genotype–phenotype correlation to muscular versus hepatic disease forms, establishing the molecular basis of CPT II deficiency.\",\n      \"evidence\": \"Transfection of mutant CPT2 cDNA in COS-1 cells with direct enzymatic activity measurement\",\n      \"pmids\": [\"9600456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which each mutation impairs catalysis unknown\", \"No crystal structure available to explain residue-specific effects\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying a pharmacological rescue pathway for CPT2 deficiency — AMPK activation by GSK773 upregulated CPT2 protein via PGC-1α/ROS/p38 MAPK in patient-derived myotubes, correcting fatty acid oxidation flux, showing CPT2 expression is amenable to transcriptional/signaling rescue.\",\n      \"evidence\": \"Patient-derived CPT2-deficient myotubes treated with AMPK agonist, FAO flux assays, siRNA epistasis\",\n      \"pmids\": [\"30007356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo efficacy of AMPK-mediated CPT2 rescue not demonstrated\", \"Whether residual mutant CPT2 protein is stabilized or new wild-type-like protein is induced unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealing a deacetylation–dimerization activation axis — low-level palmitate triggers a CDK1→SIRT3 cascade that deacetylates and dimerizes CPT2, enhancing fatty acid oxidation, establishing that CPT2 quaternary structure is regulated by acetylation status.\",\n      \"evidence\": \"In vitro kinase assays, co-IP, SIRT3 phosphorylation and CPT2 acetylation/dimerization assays in liver cells and mouse CCl4 model\",\n      \"pmids\": [\"31866205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific acetylation sites on CPT2 targeted by SIRT3 in this cascade not mapped\", \"Structural basis of how dimerization enhances activity unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovering a stabilizing ubiquitination mechanism — HRD1-mediated K48-linked ubiquitination paradoxically stabilizes CPT2 rather than promoting degradation, and its loss under glutamine deprivation destabilizes CPT2 in breast cancer cells, revealing a non-canonical ubiquitin signal.\",\n      \"evidence\": \"Reciprocal co-IP, ubiquitination assays, HRD1 knockdown/knockout in triple-negative breast cancer cells\",\n      \"pmids\": [\"33207079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which K48-ubiquitin stabilizes rather than degrades CPT2 unresolved\", \"Not validated outside breast cancer cell lines\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying direct transcriptional repression of CPT2 — ChIP demonstrated E2F2 binds the CPT2 promoter to repress transcription; E2f1/E2f2 knockout mice showed elevated CPT2, increased FAO, and resistance to hepatocarcinogenesis, linking CPT2 transcription to cell-cycle regulators and cancer.\",\n      \"evidence\": \"ChIP for E2F2 on Cpt2 promoter, E2f1/E2f2 knockout mice, liver-specific knockdown/overexpression, FAO assays\",\n      \"pmids\": [\"33771899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether E2F2 repression is cell-cycle-phase dependent unknown\", \"Other E2F family members' roles at the CPT2 promoter not systematically tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining an upstream signaling cascade for CPT2 induction — FAM3A-released ATP activates P2 receptors, driving CaM nuclear translocation where CaM co-activates FOXA2 to transcribe CPT2 in hepatocytes, establishing a complete extracellular-to-nuclear signaling pathway for CPT2 regulation.\",\n      \"evidence\": \"RNA-seq, CaM nuclear translocation assays, FOXA2 co-activator assays, FAM3A-deficient hepatocytes and mice\",\n      \"pmids\": [\"35995281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FOXA2 directly binds CPT2 promoter elements not shown by ChIP\", \"Single-lab observation awaiting replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping a Sirt3-dependent acetylation site controlling platelet survival — K79 acetylation of CPT2 (accumulating as NAD⁺/Sirt3 activity declines during storage) attenuates fatty acid oxidation, causing acylcarnitine buildup and shortened platelet lifespan, connecting CPT2 post-translational regulation to transfusion biology.\",\n      \"evidence\": \"Mass spectrometry acetylation site identification, Sirt3 activity assays, pharmacological agonists, in vitro/in vivo platelet survival assays\",\n      \"pmids\": [\"35728063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"K79 mutagenesis not performed to confirm site specificity\", \"Role of other deacetylases at this site not excluded\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying succinylation as a novel inhibitory modification — Sirt5-mediated desuccinylation at Lys424 activates CPT2; loss of Sirt5 in diabetic hearts causes Lys424 succinylation, inactivating CPT2 and impairing FAO, adding a new post-translational regulatory dimension.\",\n      \"evidence\": \"Succinylomics MS, K424R mutagenesis, enzymatic activity assays, cardiac-specific Sirt5 knockout and overexpression mice\",\n      \"pmids\": [\"38718533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Succinyl-CoA-dependent succinylation writer not identified\", \"Whether Lys424 succinylation occurs in non-cardiac tissues unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that CPT2-dependent FAO is dispensable for humoral immunity — lymphocyte-specific CPT2 knockout mice showed markedly reduced fatty acid-derived citrate in B cells yet normal B cell development, germinal center reactions, and antibody production, delimiting the tissues in which CPT2 is functionally essential.\",\n      \"evidence\": \"Lymphocyte-specific CPT2 knockout mice, ¹³C isotope tracing, flow cytometry, in vivo antigen challenge\",\n      \"pmids\": [\"39258879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CPT2-independent compensatory FAO pathways exist in B cells not investigated\", \"T cell-specific functional consequences not deeply characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing a degradation-promoting deacetylation — SIRT2 deacetylates CPT2 at Lys239, promoting ubiquitination and degradation, thereby suppressing FAO in the diabetic heart — in contrast to SIRT3-mediated deacetylation which activates CPT2, demonstrating sirtuin-specific opposing outcomes.\",\n      \"evidence\": \"Cardiac-specific SIRT2 overexpression/knockdown in STZ/HFD diabetic mice, K239 mutagenesis, ubiquitination assays\",\n      \"pmids\": [\"39781464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase mediating SIRT2-induced CPT2 ubiquitination not identified\", \"How K239 deacetylation exposes a degron is structurally unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of CPT2 — ideally with bound substrate or acyl-carnitine — is needed to explain how specific lysine modifications (K79, K239, K424) and disease mutations (E174K, F383Y) affect catalysis and dimerization, and how the outer-membrane malonyl-CoA-binding protein confers inhibitor sensitivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of mammalian CPT2 published\", \"Molecular identity of the outer-membrane malonyl-CoA-binding partner remains unresolved\", \"Relative contributions of competing sirtuin pathways in vivo across tissues not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0016740\",\n        \"supporting_discovery_ids\": [0, 1, 6, 7, 8, 9]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005739\",\n        \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 7, 9]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1430728\",\n        \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 9, 13]\n      },\n      {\n        \"term_id\": \"R-HSA-1643685\",\n        \"supporting_discovery_ids\": [8, 14]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SIRT3\",\n      \"SIRT2\",\n      \"SIRT5\",\n      \"HRD1\",\n      \"MUL1\",\n      \"E2F2\",\n      \"FOXA2\",\n      \"CDK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}