{"gene":"ME2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2023,"finding":"SIRT5 acts as a desuccinylase for ME2, removing succinylation at lysine 346. Glutamine deprivation enhances the SIRT5–ME2 interaction, promoting desuccinylation and activating ME2 enzymatic activity. Activated ME2 enhances mitochondrial respiration to support cell proliferation under glutamine deficiency.","method":"Co-immunoprecipitation, site-directed mutagenesis (K346), enzymatic activity assays, mitochondrial respiration measurement, in vitro and in vivo cancer models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying writer/reader, mutagenesis of modification site, multiple orthogonal functional assays in one study","pmids":["38007551"],"is_preprint":false},{"year":2024,"finding":"AKT1 phosphorylates the full-length cytoplasmic isoform of ME2 (ME2fl) at serine 9 in the mitochondrial localization signal peptide, preventing mitochondrial translocation. Cytoplasmic ME2fl functions as a scaffold assembling glycolytic enzymes PFKL, GAPDH, PKM2, and LDHA to promote glycolysis, thereby mediating a metabolic switch from mitochondrial TCA-cycle metabolism to aerobic glycolysis in tumor cells.","method":"Co-immunoprecipitation, site-directed mutagenesis (S9), subcellular fractionation, glycolytic flux assays, in vitro and in vivo tumor models, phosphorylation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, fractionation, functional rescue) in a single rigorous study with in vivo validation","pmids":["38263319"],"is_preprint":false},{"year":2025,"finding":"ACAT1 acetylates ME2 at lysine 156, potentiating ME2 enzymatic activity and facilitating pyruvate/lactate production from glutamine-derived malate. Decreased intracellular glucose (triggered by chemotherapy) drives this ACAT1-mediated ME2 acetylation, and ME2-derived lactate promotes protein lactylation involved in homologous recombination repair, contributing to chemoresistance.","method":"Co-immunoprecipitation, site-directed mutagenesis (K156), enzymatic activity assays, glucose uptake assays, in vitro and in vivo chemoresistance models, metabolomic analyses","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified writer (ACAT1), modification site (K156) by mutagenesis, functional consequence assayed by multiple orthogonal methods in vitro and in vivo","pmids":["39951294"],"is_preprint":false},{"year":2024,"finding":"PRMT1 methylates ME2 (at arginine, with mutation at lysine 67 shown to mimic activated state), activating ME2 enzymatic activity and enhancing mitochondrial respiration to promote hepatocellular carcinoma cell growth and migration. ME2 was shown to directly interact with PRMT1 by co-immunoprecipitation.","method":"Co-immunoprecipitation, site-directed mutagenesis (R67K), enzymatic activity assays, mitochondrial respiration measurement, cell proliferation and migration assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying writer, mutagenesis of modification site, functional assays; single lab, some mechanistic details compressed in abstract","pmids":["39528487"],"is_preprint":false},{"year":2015,"finding":"The natural compound embonic acid (EA) allosterically inhibits mitochondrial NAD(P)+-dependent malic enzyme ME2 with an in vitro IC50 of ~1.4 µM. Mutagenesis and binding studies localized the EA binding site to the fumarate binding site or dimer interface, distinct from the catalytic active site. EA inhibition of ME2 in H1299 cancer cells induced cellular senescence via a p53-independent pathway.","method":"In vitro enzymatic inhibition assay, site-directed mutagenesis, thermal shift binding assay, shRNA knockdown, cellular senescence assay","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay with mutagenesis identifying allosteric binding site, plus cellular functional validation; single lab with multiple orthogonal methods","pmids":["26008970"],"is_preprint":false},{"year":2014,"finding":"NPD389 is an uncompetitive inhibitor of ME2 with respect to the substrate NAD+ and a mixed-type inhibitor with respect to L-malate, acting in a fast-binding mode. This was established by enzyme kinetics analysis of purified recombinant human ME2.","method":"High-throughput screening, enzyme kinetics analysis, thermal shift assay with purified recombinant human ME2","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with kinetics characterization; single lab, two orthogonal methods (kinetics + thermal shift)","pmids":["24681895"],"is_preprint":false},{"year":2009,"finding":"Mitochondrial ME2 has distinct kinetic properties from cytosolic ME1 and the other mitochondrial ME3: ME2 uses either NAD or NADP as cofactor, has a high Km for malate, and is allosterically activated by fumarate and inhibited by ATP. ME2 activity was directly detected and confirmed by immunoblotting in human, rat, and mouse pancreatic islets and INS-1 832/13 insulinoma cells.","method":"Spectrophotometric enzyme activity assay exploiting distinct kinetics, immunoblotting, tissue fractionation","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with kinetic characterization across multiple species and cell types; single lab, two orthogonal methods","pmids":["19691144"],"is_preprint":false},{"year":2023,"finding":"ME2 promotes hepatocellular carcinoma cell migration and invasion by producing pyruvate, which directly binds to β-catenin and increases β-catenin protein levels. Pyruvate treatment rescued migration defects in ME2-depleted cells.","method":"ME2 knockdown and overexpression, cell migration/invasion assays, pyruvate rescue experiment, β-catenin binding and protein level measurements","journal":"Metabolites","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined phenotype, rescue experiment linking pyruvate to β-catenin; single lab, multiple orthogonal approaches","pmids":["37110198"],"is_preprint":false},{"year":2023,"finding":"ME2 inhibition (by silencing or allosteric inhibitor disodium embonate) in AML cells decreases pyruvate and NADH, reducing ATP production via oxidative phosphorylation, and decreases NADPH leading to increased ROS and oxidative stress, ultimately inducing apoptosis. ME2 silencing also inhibited xenotransplanted human AML cell growth in vivo.","method":"shRNA silencing, allosteric inhibitor treatment, metabolite measurements (pyruvate, NADH, NADPH, ATP, ROS), xenograft mouse model","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/KD with defined metabolic phenotype readouts and in vivo validation; single lab, multiple functional assays","pmids":["37079187"],"is_preprint":false},{"year":2021,"finding":"ME2 inhibits mitochondrial ROS production and AMPK phosphorylation in glioblastoma cells, leading to SREBP-1 maturation and nuclear localization and enhancing the ACSS2 lipogenesis pathway. ME2 also promotes proneural-to-mesenchymal transition by upregulating mesenchymal markers (N-cadherin, vimentin, YKL40, MET) and downregulating OLIG2.","method":"ME2 overexpression and knockdown, ROS measurement, AMPK phosphorylation assay, SREBP-1 localization, gene expression analysis, cell migration/invasion assays","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional assays with pathway placement but no direct binding or mutagenesis; mechanism is correlative rather than biochemically reconstituted","pmids":["34381734"],"is_preprint":false},{"year":2023,"finding":"ME2 is a direct target of miR-214-3p, as established by dual luciferase reporter assay. Overexpression of ME2 ameliorated ferroptosis and cellular damage induced by miR-214-3p in cardiomyocytes, while ME2 depletion compromised the protective effects of miR-214-3p inhibitor against hypoxic injury.","method":"Dual luciferase reporter assay, ME2 overexpression and depletion in neonatal rat cardiomyocytes, hypoxia model, ferroptosis markers, mouse MI model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA target validation by reporter assay, functional rescue experiment; single lab with multiple orthogonal approaches","pmids":["37087800"],"is_preprint":false},{"year":2024,"finding":"A homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in ME2 results in truncated, unstable ME2 protein and is associated with a neurodevelopmental disorder in a human patient. Deletion of the yeast ortholog of ME2 caused growth arrest rescued by overexpression of human ME2, supporting ME2's essential role in mitochondrial function.","method":"Whole exome sequencing, in vitro expression of truncated protein, yeast complementation (deletion + rescue by human ME2 overexpression)","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation in yeast ortholog plus in vitro protein stability; single study, two orthogonal approaches","pmids":["39401966"],"is_preprint":false},{"year":1998,"finding":"Murine E2-C (mE2-C), a cyclin-selective ubiquitin conjugating enzyme, is required for in vitro ubiquitination and degradation of cyclin B in human HeLa cell extracts. A dominant-negative form created by mutating the catalytic cysteine to serine blocked cyclin B ubiquitination and degradation. mE2-C expression varies with the cell cycle.","method":"Dominant-negative mutagenesis (catalytic cysteine to serine), in vitro ubiquitination assay in HeLa cell extracts, cell cycle expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with active-site mutagenesis; single lab; NOTE: mE2-C is a ubiquitin-conjugating enzyme (UBE2C/UBCH10), distinct from malic enzyme ME2 — this paper is about a different protein and should not be attributed to the malic enzyme ME2 gene","pmids":["9798675"],"is_preprint":false},{"year":2025,"finding":"CYP4F11 prevents ubiquitin-proteasomal degradation of ME2, stabilizing ME2 protein levels. miR-195 suppresses CYP4F11, which leads to ME2 degradation and disrupts mitochondrial malate metabolism. Rescue experiments confirmed ME2 mediates CYP4F11's oncogenic effects in NSCLC.","method":"3'-UTR luciferase reporter assay (miR-195/CYP4F11), CYP4F11 knockdown and overexpression, ME2 protein stability assay, rescue experiments, metabolomic analysis","journal":"Frontiers of medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional rescue establishes pathway position but the mechanism of ME2 stabilization by CYP4F11 is not biochemically detailed in the abstract","pmids":["41359237"],"is_preprint":false},{"year":1985,"finding":"Genetic linkage analysis placed the ME2 locus on the short arm of chromosome 6, closely linked to coagulation factor XIIIA (F13A) with a maximum lod score of 4.33 at recombination fraction 0.10. Map order established as GLO1–HLA–F13A–ME2.","method":"Family-based genetic linkage analysis (18 informative families, 54 children), lod score calculation","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — classical genetic mapping; replicated across families, but chromosomal assignment only (no molecular mechanism)","pmids":["2860058"],"is_preprint":false},{"year":2024,"finding":"In ME2-deficient pancreatic cancer cells (with co-deletion of SMAD4/ME2), ME3 is upregulated to compensate for ROS clearance. Targeted siRNA knockdown of ME3 in these ME2-deficient cells inhibited their capacity to clear ROS and, combined with doxorubicin-induced ROS increase, led to apoptosis — demonstrating collateral lethality exploiting ME2 loss.","method":"siRNA knockdown of ME3 in ME2-deficient PC cells, ROS measurement, apoptosis assay, targeted DNA nanostructure delivery in vivo","journal":"Nano letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic epistasis (ME2 loss/ME3 compensation) demonstrated by functional assay in cancer cells; single study, mechanism inferred from compensatory relationship","pmids":["39602246"],"is_preprint":false}],"current_model":"Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to pyruvate using NAD(P)+ as cofactor (allosterically activated by fumarate, inhibited by ATP); its activity is regulated by post-translational modifications — SIRT5-mediated desuccinylation at K346 activates it under glutamine deprivation, ACAT1-mediated acetylation at K156 activates it under low-glucose conditions to support lactate production and chemoresistance, and PRMT1-mediated methylation similarly activates it in hepatocellular carcinoma — while AKT1 phosphorylation of a cytoplasmic full-length isoform (ME2fl) at S9 prevents mitochondrial import and repurposes ME2fl as a scaffold for glycolytic enzyme assembly, thereby switching cellular metabolism toward aerobic glycolysis; loss-of-function causes neurodevelopmental disorder in humans and growth arrest in yeast rescued by human ME2 complementation."},"narrative":{"mechanistic_narrative":"ME2 is a mitochondrial NAD(P)+-dependent malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate, with distinct kinetics from its paralogs (high Km for malate, dual NAD/NADP cofactor use, allosteric activation by fumarate and inhibition by ATP), and functions across multiple tissues including pancreatic islets [PMID:19691144]. By generating pyruvate and reducing equivalents, ME2 sustains mitochondrial respiration, ATP production via oxidative phosphorylation, and NADPH-dependent ROS clearance, such that its loss raises oxidative stress and triggers apoptosis [PMID:37079187]. ME2 activity is tuned by a convergent set of activating post-translational modifications gated by nutrient state: SIRT5-mediated desuccinylation at K346 activates ME2 under glutamine deprivation to support proliferation [PMID:38007551], ACAT1-mediated acetylation at K156 activates it under low glucose to drive pyruvate/lactate output and chemoresistance [PMID:39951294], and PRMT1-mediated methylation activates it to promote hepatocellular carcinoma growth [PMID:39528487]. Phosphorylation of the full-length cytoplasmic isoform (ME2fl) at S9 by AKT1 blocks its mitochondrial import and converts it into a scaffold that assembles glycolytic enzymes (PFKL, GAPDH, PKM2, LDHA), switching metabolism toward aerobic glycolysis [PMID:38263319]. ME2-derived pyruvate also stabilizes β-catenin to promote migration and invasion [PMID:37110198]. A homozygous frameshift variant producing truncated, unstable ME2 protein causes a human neurodevelopmental disorder, and the growth arrest of yeast lacking the ME2 ortholog is rescued by human ME2, establishing an essential mitochondrial role [PMID:39401966]. The enzyme is allosterically druggable at a site distinct from the active site (embonic acid) and by active-site-directed inhibitors (NPD389) [PMID:26008970, PMID:24681895].","teleology":[{"year":1985,"claim":"Before molecular characterization, the question was simply where ME2 resides in the genome; linkage mapping anchored the locus, providing the genetic foothold for later study.","evidence":"Family-based genetic linkage analysis placing ME2 on chromosome 6p near F13A","pmids":["2860058"],"confidence":"Medium","gaps":["Chromosomal assignment only, no molecular or functional mechanism","No protein-level characterization"]},{"year":2009,"claim":"It was unclear how mitochondrial ME2 differs functionally from its paralogs; kinetic profiling established ME2 as a dual-cofactor, fumarate-activated, ATP-inhibited enzyme distinct from ME1 and ME3.","evidence":"Spectrophotometric enzyme activity and immunoblotting across human, rat, mouse islets and INS-1 cells","pmids":["19691144"],"confidence":"Medium","gaps":["No structural basis for cofactor promiscuity or allosteric regulation","Physiological role in islets not resolved"]},{"year":2015,"claim":"Whether ME2 could be pharmacologically targeted and at what site was unknown; embonic acid was shown to allosterically inhibit ME2 at the fumarate site/dimer interface, distinct from the catalytic site, and induce p53-independent senescence.","evidence":"In vitro enzymatic inhibition, mutagenesis, thermal shift binding, shRNA knockdown and senescence assays in H1299 cells","pmids":["26008970","24681895"],"confidence":"High","gaps":["Selectivity over ME1/ME3 not fully established","Off-target cellular effects of allosteric inhibition unclear"]},{"year":2023,"claim":"The first activating PTM regulation of ME2 was unknown; SIRT5 desuccinylation at K346 was identified as a nutrient-gated activation switch coupling glutamine availability to mitochondrial respiration.","evidence":"Reciprocal Co-IP, K346 mutagenesis, enzymatic and respiration assays, in vitro/in vivo cancer models","pmids":["38007551"],"confidence":"High","gaps":["Succinyltransferase 'writer' not identified","Stoichiometry of K346 succinylation in vivo unknown"]},{"year":2023,"claim":"How ME2 enzymatic output feeds cellular signaling and survival was open; loss-of-function studies showed ME2 supplies pyruvate that stabilizes β-catenin to drive migration, and sustains OXPHOS/NADPH to suppress ROS and apoptosis.","evidence":"Knockdown/overexpression with pyruvate rescue, β-catenin assays; shRNA silencing and allosteric inhibitor with metabolite readouts and AML xenografts","pmids":["37110198","37079187"],"confidence":"Medium","gaps":["Mechanism of pyruvate–β-catenin interaction not structurally defined","Tissue specificity of metabolic vulnerability unclear"]},{"year":2024,"claim":"Whether ME2 has a moonlighting non-catalytic function was unknown; AKT1 phosphorylation at S9 was shown to block mitochondrial import and repurpose cytoplasmic ME2fl as a glycolytic-enzyme scaffold, defining a metabolic switch toward aerobic glycolysis.","evidence":"Co-IP, S9 mutagenesis, subcellular fractionation, glycolytic flux assays, in vivo tumor models","pmids":["38263319"],"confidence":"High","gaps":["Structural basis of the glycolytic scaffold assembly not resolved","Relative abundance of ME2fl scaffold vs mitochondrial pool not quantified"]},{"year":2024,"claim":"Whether arginine methylation regulates ME2 and disease relevance of ME2 loss were open; PRMT1 methylation was shown to activate ME2 in HCC, and a human frameshift variant plus yeast complementation established ME2 as essential for mitochondrial function and linked to neurodevelopmental disease.","evidence":"Co-IP and mutagenesis with respiration/proliferation assays (PRMT1); whole exome sequencing, truncated protein expression, yeast deletion/rescue","pmids":["39528487","39401966"],"confidence":"Medium","gaps":["Exact methylated residue(s) not definitively mapped","Single patient; genotype-phenotype spectrum unknown","Mechanism connecting ME2 deficiency to neurodevelopment unclear"]},{"year":2025,"claim":"How ME2 activity is coupled to chemoresistance was unknown; ACAT1 acetylation at K156 was shown to activate ME2 under low glucose, driving lactate-dependent protein lactylation that supports homologous recombination repair.","evidence":"Co-IP, K156 mutagenesis, enzymatic/glucose-uptake assays, metabolomics, in vitro/in vivo chemoresistance models","pmids":["39951294"],"confidence":"High","gaps":["Direct lactylation targets in HR repair not enumerated","Interplay between K156, K346 and other PTMs not resolved"]},{"year":null,"claim":"An integrated model of how the multiple activating PTMs (succinylation, acetylation, methylation), AKT1 phosphorylation, and protein-stability control (CYP4F11) are coordinated under specific physiological conditions, and how ME2 dysfunction produces neurodevelopmental disease, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the regulated enzyme or its scaffold form","PTM hierarchy and crosstalk uncharacterized","Mechanistic link between ME2 loss and the neurodevelopmental phenotype not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[6,0,2,3]},{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6,1,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,1,8]}],"complexes":[],"partners":["SIRT5","ACAT1","PRMT1","AKT1","PFKL","GAPDH","PKM2","LDHA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23368","full_name":"NAD-dependent malic enzyme, mitochondrial","aliases":["Malic enzyme 2"],"length_aa":584,"mass_kda":65.4,"function":"NAD-dependent mitochondrial malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P23368/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ME2","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"HSPB11","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ME2","total_profiled":1310},"omim":[{"mim_id":"620057","title":"PHD FINGER PROTEIN 7; PHF7","url":"https://www.omim.org/entry/620057"},{"mim_id":"619348","title":"ANKYRIN REPEAT- AND LEM DOMAIN-CONTAINING PROTEIN 1; ANKLE1","url":"https://www.omim.org/entry/619348"},{"mim_id":"616581","title":"LYSINE DEMETHYLASE 4E; KDM4E","url":"https://www.omim.org/entry/616581"},{"mim_id":"609764","title":"LYSINE DEMETHYLASE 4A; KDM4A","url":"https://www.omim.org/entry/609764"},{"mim_id":"606337","title":"PROTOCADHERIN-BETA 11; PCDHB11","url":"https://www.omim.org/entry/606337"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":86.4}],"url":"https://www.proteinatlas.org/search/ME2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P23368","domains":[{"cath_id":"3.40.50.10380","chopping":"104-274","consensus_level":"medium","plddt":96.7633,"start":104,"end":274},{"cath_id":"3.40.50.720","chopping":"282-468_486-512","consensus_level":"high","plddt":95.6578,"start":282,"end":512}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23368","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23368-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23368-F1-predicted_aligned_error_v6.png","plddt_mean":94.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ME2","jax_strain_url":"https://www.jax.org/strain/search?query=ME2"},"sequence":{"accession":"P23368","fasta_url":"https://rest.uniprot.org/uniprotkb/P23368.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23368/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23368"}},"corpus_meta":[{"pmid":"3930657","id":"PMC_3930657","title":"Conjugal transfer from Streptococcus lactis ME2 of plasmids encoding phage resistance, nisin resistance and lactose-fermenting ability: evidence for a high-frequency conjugative plasmid responsible for abortive infection of virulent bacteriophage.","date":"1985","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/3930657","citation_count":88,"is_preprint":false},{"pmid":"9798675","id":"PMC_9798675","title":"EWS/FLI1 up regulates mE2-C, a cyclin-selective ubiquitin conjugating enzyme involved in cyclin B destruction.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9798675","citation_count":82,"is_preprint":false},{"pmid":"21225028","id":"PMC_21225028","title":"Me2-NHC based robust Ir catalyst for efficient water oxidation.","date":"2011","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21225028","citation_count":73,"is_preprint":false},{"pmid":"1429469","id":"PMC_1429469","title":"Molecular characterization of a second abortive phage resistance gene present in Lactococcus lactis subsp. lactis ME2.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1429469","citation_count":54,"is_preprint":false},{"pmid":"38007551","id":"PMC_38007551","title":"SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/38007551","citation_count":52,"is_preprint":false},{"pmid":"11448932","id":"PMC_11448932","title":"In vivo antitumor activity of bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) (METVAN [VO(SO4)(Me2-Phen)2]).","date":"2001","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/11448932","citation_count":48,"is_preprint":false},{"pmid":"2841286","id":"PMC_2841286","title":"Restriction and modification activities from Streptococcus lactis ME2 are encoded by a self-transmissible plasmid, pTN20, that forms cointegrates during mobilization of lactose-fermenting ability.","date":"1988","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2841286","citation_count":44,"is_preprint":false},{"pmid":"19084597","id":"PMC_19084597","title":"Combination of 2-methoxyestradiol (2-ME2) and eugenol for apoptosis induction synergistically in androgen independent prostate cancer cells.","date":"2008","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19084597","citation_count":41,"is_preprint":false},{"pmid":"7984047","id":"PMC_7984047","title":"Expression of basic-helix-loop-helix transcription factor ME2 during brain development and in the regions of neuronal plasticity in the adult brain.","date":"1994","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7984047","citation_count":40,"is_preprint":false},{"pmid":"9632694","id":"PMC_9632694","title":"The effect of Me2+ cofactors at the initial stages of V(D)J recombination.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9632694","citation_count":38,"is_preprint":false},{"pmid":"38263319","id":"PMC_38263319","title":"AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38263319","citation_count":35,"is_preprint":false},{"pmid":"14670179","id":"PMC_14670179","title":"2-Methoxyestradiol exhibits a biphasic effect on VEGF-A in tumor cells and upregulation is mediated through ER-alpha: a possible signaling pathway associated with the impact of 2-ME2 on proliferative cells.","date":"2003","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14670179","citation_count":34,"is_preprint":false},{"pmid":"25557135","id":"PMC_25557135","title":"Alkane metathesis with the tantalum methylidene [(≡SiO)Ta(═CH2)Me2]/[(≡SiO)2Ta(═CH2)Me] generated from well-defined surface organometallic complex [(≡SiO)Ta(V)Me4].","date":"2015","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/25557135","citation_count":32,"is_preprint":false},{"pmid":"7200884","id":"PMC_7200884","title":"The structure of the EF-Tu . GDP . Me2+ complex.","date":"1982","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7200884","citation_count":30,"is_preprint":false},{"pmid":"26475199","id":"PMC_26475199","title":"Enhanced cytosolic NADP-ME2 activity in A. thaliana affects plant development, stress tolerance and specific diurnal and nocturnal cellular processes.","date":"2015","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/26475199","citation_count":29,"is_preprint":false},{"pmid":"34480757","id":"PMC_34480757","title":"Plant defense compound triggers mycotoxin synthesis by regulating H2B ub1 and H3K4 me2/3 deposition.","date":"2021","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/34480757","citation_count":29,"is_preprint":false},{"pmid":"39951294","id":"PMC_39951294","title":"ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39951294","citation_count":27,"is_preprint":false},{"pmid":"7769987","id":"PMC_7769987","title":"Differential expression and distinct DNA-binding specificity of ME1a and ME2 suggest a unique role during differentiation and neuronal plasticity.","date":"1995","source":"Brain research. 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The effect of trypsin on the purified enzyme.","date":"1976","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/131581","citation_count":15,"is_preprint":false},{"pmid":"2860058","id":"PMC_2860058","title":"Linkage between the loci for mitochondrial malic enzyme (ME2) and coagulation factor XIIIA subunit (F13A).","date":"1985","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2860058","citation_count":13,"is_preprint":false},{"pmid":"17039388","id":"PMC_17039388","title":"Innovative effect of illite on improved microbiological conversion of L-tyrosine to 3,4 dihydroxy phenyl L-alanine (L-DOPA) by Aspergillus oryzae ME2 under acidic reaction conditions.","date":"2006","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17039388","citation_count":13,"is_preprint":false},{"pmid":"11378580","id":"PMC_11378580","title":"Apoptosis inducing novel anti-leukemic agent, bis(4,7-dimethyl-1,10 phenanthroline) sulfatooxovanadium(IV) 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methylation of ME2 promotes hepatocellular carcinoma growth by inhibiting ubiquitination.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39528487","citation_count":3,"is_preprint":false},{"pmid":"37110198","id":"PMC_37110198","title":"ME2 Promotes Hepatocellular Carcinoma Cell Migration through Pyruvate.","date":"2023","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/37110198","citation_count":3,"is_preprint":false},{"pmid":"29779113","id":"PMC_29779113","title":"Preparation and Properties of Nanoparticles, tRNA-Bivalent Metal Cation (Me2+) Complexes, and Prospects of Their Practical Use.","date":"2018","source":"Doklady. 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Glutamine deprivation enhances the SIRT5–ME2 interaction, promoting desuccinylation and activating ME2 enzymatic activity. Activated ME2 enhances mitochondrial respiration to support cell proliferation under glutamine deficiency.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K346), enzymatic activity assays, mitochondrial respiration measurement, in vitro and in vivo cancer models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying writer/reader, mutagenesis of modification site, multiple orthogonal functional assays in one study\",\n      \"pmids\": [\"38007551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AKT1 phosphorylates the full-length cytoplasmic isoform of ME2 (ME2fl) at serine 9 in the mitochondrial localization signal peptide, preventing mitochondrial translocation. Cytoplasmic ME2fl functions as a scaffold assembling glycolytic enzymes PFKL, GAPDH, PKM2, and LDHA to promote glycolysis, thereby mediating a metabolic switch from mitochondrial TCA-cycle metabolism to aerobic glycolysis in tumor cells.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (S9), subcellular fractionation, glycolytic flux assays, in vitro and in vivo tumor models, phosphorylation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, fractionation, functional rescue) in a single rigorous study with in vivo validation\",\n      \"pmids\": [\"38263319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACAT1 acetylates ME2 at lysine 156, potentiating ME2 enzymatic activity and facilitating pyruvate/lactate production from glutamine-derived malate. Decreased intracellular glucose (triggered by chemotherapy) drives this ACAT1-mediated ME2 acetylation, and ME2-derived lactate promotes protein lactylation involved in homologous recombination repair, contributing to chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K156), enzymatic activity assays, glucose uptake assays, in vitro and in vivo chemoresistance models, metabolomic analyses\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified writer (ACAT1), modification site (K156) by mutagenesis, functional consequence assayed by multiple orthogonal methods in vitro and in vivo\",\n      \"pmids\": [\"39951294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRMT1 methylates ME2 (at arginine, with mutation at lysine 67 shown to mimic activated state), activating ME2 enzymatic activity and enhancing mitochondrial respiration to promote hepatocellular carcinoma cell growth and migration. ME2 was shown to directly interact with PRMT1 by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (R67K), enzymatic activity assays, mitochondrial respiration measurement, cell proliferation and migration assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying writer, mutagenesis of modification site, functional assays; single lab, some mechanistic details compressed in abstract\",\n      \"pmids\": [\"39528487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The natural compound embonic acid (EA) allosterically inhibits mitochondrial NAD(P)+-dependent malic enzyme ME2 with an in vitro IC50 of ~1.4 µM. Mutagenesis and binding studies localized the EA binding site to the fumarate binding site or dimer interface, distinct from the catalytic active site. EA inhibition of ME2 in H1299 cancer cells induced cellular senescence via a p53-independent pathway.\",\n      \"method\": \"In vitro enzymatic inhibition assay, site-directed mutagenesis, thermal shift binding assay, shRNA knockdown, cellular senescence assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay with mutagenesis identifying allosteric binding site, plus cellular functional validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26008970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NPD389 is an uncompetitive inhibitor of ME2 with respect to the substrate NAD+ and a mixed-type inhibitor with respect to L-malate, acting in a fast-binding mode. This was established by enzyme kinetics analysis of purified recombinant human ME2.\",\n      \"method\": \"High-throughput screening, enzyme kinetics analysis, thermal shift assay with purified recombinant human ME2\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with kinetics characterization; single lab, two orthogonal methods (kinetics + thermal shift)\",\n      \"pmids\": [\"24681895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mitochondrial ME2 has distinct kinetic properties from cytosolic ME1 and the other mitochondrial ME3: ME2 uses either NAD or NADP as cofactor, has a high Km for malate, and is allosterically activated by fumarate and inhibited by ATP. ME2 activity was directly detected and confirmed by immunoblotting in human, rat, and mouse pancreatic islets and INS-1 832/13 insulinoma cells.\",\n      \"method\": \"Spectrophotometric enzyme activity assay exploiting distinct kinetics, immunoblotting, tissue fractionation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with kinetic characterization across multiple species and cell types; single lab, two orthogonal methods\",\n      \"pmids\": [\"19691144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ME2 promotes hepatocellular carcinoma cell migration and invasion by producing pyruvate, which directly binds to β-catenin and increases β-catenin protein levels. Pyruvate treatment rescued migration defects in ME2-depleted cells.\",\n      \"method\": \"ME2 knockdown and overexpression, cell migration/invasion assays, pyruvate rescue experiment, β-catenin binding and protein level measurements\",\n      \"journal\": \"Metabolites\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined phenotype, rescue experiment linking pyruvate to β-catenin; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"37110198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ME2 inhibition (by silencing or allosteric inhibitor disodium embonate) in AML cells decreases pyruvate and NADH, reducing ATP production via oxidative phosphorylation, and decreases NADPH leading to increased ROS and oxidative stress, ultimately inducing apoptosis. ME2 silencing also inhibited xenotransplanted human AML cell growth in vivo.\",\n      \"method\": \"shRNA silencing, allosteric inhibitor treatment, metabolite measurements (pyruvate, NADH, NADPH, ATP, ROS), xenograft mouse model\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/KD with defined metabolic phenotype readouts and in vivo validation; single lab, multiple functional assays\",\n      \"pmids\": [\"37079187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ME2 inhibits mitochondrial ROS production and AMPK phosphorylation in glioblastoma cells, leading to SREBP-1 maturation and nuclear localization and enhancing the ACSS2 lipogenesis pathway. ME2 also promotes proneural-to-mesenchymal transition by upregulating mesenchymal markers (N-cadherin, vimentin, YKL40, MET) and downregulating OLIG2.\",\n      \"method\": \"ME2 overexpression and knockdown, ROS measurement, AMPK phosphorylation assay, SREBP-1 localization, gene expression analysis, cell migration/invasion assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional assays with pathway placement but no direct binding or mutagenesis; mechanism is correlative rather than biochemically reconstituted\",\n      \"pmids\": [\"34381734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ME2 is a direct target of miR-214-3p, as established by dual luciferase reporter assay. Overexpression of ME2 ameliorated ferroptosis and cellular damage induced by miR-214-3p in cardiomyocytes, while ME2 depletion compromised the protective effects of miR-214-3p inhibitor against hypoxic injury.\",\n      \"method\": \"Dual luciferase reporter assay, ME2 overexpression and depletion in neonatal rat cardiomyocytes, hypoxia model, ferroptosis markers, mouse MI model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA target validation by reporter assay, functional rescue experiment; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37087800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in ME2 results in truncated, unstable ME2 protein and is associated with a neurodevelopmental disorder in a human patient. Deletion of the yeast ortholog of ME2 caused growth arrest rescued by overexpression of human ME2, supporting ME2's essential role in mitochondrial function.\",\n      \"method\": \"Whole exome sequencing, in vitro expression of truncated protein, yeast complementation (deletion + rescue by human ME2 overexpression)\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation in yeast ortholog plus in vitro protein stability; single study, two orthogonal approaches\",\n      \"pmids\": [\"39401966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Murine E2-C (mE2-C), a cyclin-selective ubiquitin conjugating enzyme, is required for in vitro ubiquitination and degradation of cyclin B in human HeLa cell extracts. A dominant-negative form created by mutating the catalytic cysteine to serine blocked cyclin B ubiquitination and degradation. mE2-C expression varies with the cell cycle.\",\n      \"method\": \"Dominant-negative mutagenesis (catalytic cysteine to serine), in vitro ubiquitination assay in HeLa cell extracts, cell cycle expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with active-site mutagenesis; single lab; NOTE: mE2-C is a ubiquitin-conjugating enzyme (UBE2C/UBCH10), distinct from malic enzyme ME2 — this paper is about a different protein and should not be attributed to the malic enzyme ME2 gene\",\n      \"pmids\": [\"9798675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CYP4F11 prevents ubiquitin-proteasomal degradation of ME2, stabilizing ME2 protein levels. miR-195 suppresses CYP4F11, which leads to ME2 degradation and disrupts mitochondrial malate metabolism. Rescue experiments confirmed ME2 mediates CYP4F11's oncogenic effects in NSCLC.\",\n      \"method\": \"3'-UTR luciferase reporter assay (miR-195/CYP4F11), CYP4F11 knockdown and overexpression, ME2 protein stability assay, rescue experiments, metabolomic analysis\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional rescue establishes pathway position but the mechanism of ME2 stabilization by CYP4F11 is not biochemically detailed in the abstract\",\n      \"pmids\": [\"41359237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Genetic linkage analysis placed the ME2 locus on the short arm of chromosome 6, closely linked to coagulation factor XIIIA (F13A) with a maximum lod score of 4.33 at recombination fraction 0.10. Map order established as GLO1–HLA–F13A–ME2.\",\n      \"method\": \"Family-based genetic linkage analysis (18 informative families, 54 children), lod score calculation\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — classical genetic mapping; replicated across families, but chromosomal assignment only (no molecular mechanism)\",\n      \"pmids\": [\"2860058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In ME2-deficient pancreatic cancer cells (with co-deletion of SMAD4/ME2), ME3 is upregulated to compensate for ROS clearance. Targeted siRNA knockdown of ME3 in these ME2-deficient cells inhibited their capacity to clear ROS and, combined with doxorubicin-induced ROS increase, led to apoptosis — demonstrating collateral lethality exploiting ME2 loss.\",\n      \"method\": \"siRNA knockdown of ME3 in ME2-deficient PC cells, ROS measurement, apoptosis assay, targeted DNA nanostructure delivery in vivo\",\n      \"journal\": \"Nano letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic epistasis (ME2 loss/ME3 compensation) demonstrated by functional assay in cancer cells; single study, mechanism inferred from compensatory relationship\",\n      \"pmids\": [\"39602246\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to pyruvate using NAD(P)+ as cofactor (allosterically activated by fumarate, inhibited by ATP); its activity is regulated by post-translational modifications — SIRT5-mediated desuccinylation at K346 activates it under glutamine deprivation, ACAT1-mediated acetylation at K156 activates it under low-glucose conditions to support lactate production and chemoresistance, and PRMT1-mediated methylation similarly activates it in hepatocellular carcinoma — while AKT1 phosphorylation of a cytoplasmic full-length isoform (ME2fl) at S9 prevents mitochondrial import and repurposes ME2fl as a scaffold for glycolytic enzyme assembly, thereby switching cellular metabolism toward aerobic glycolysis; loss-of-function causes neurodevelopmental disorder in humans and growth arrest in yeast rescued by human ME2 complementation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ME2 is a mitochondrial NAD(P)+-dependent malic enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate, with distinct kinetics from its paralogs (high Km for malate, dual NAD/NADP cofactor use, allosteric activation by fumarate and inhibition by ATP), and functions across multiple tissues including pancreatic islets [#6]. By generating pyruvate and reducing equivalents, ME2 sustains mitochondrial respiration, ATP production via oxidative phosphorylation, and NADPH-dependent ROS clearance, such that its loss raises oxidative stress and triggers apoptosis [#8]. ME2 activity is tuned by a convergent set of activating post-translational modifications gated by nutrient state: SIRT5-mediated desuccinylation at K346 activates ME2 under glutamine deprivation to support proliferation [#0], ACAT1-mediated acetylation at K156 activates it under low glucose to drive pyruvate/lactate output and chemoresistance [#2], and PRMT1-mediated methylation activates it to promote hepatocellular carcinoma growth [#3]. Phosphorylation of the full-length cytoplasmic isoform (ME2fl) at S9 by AKT1 blocks its mitochondrial import and converts it into a scaffold that assembles glycolytic enzymes (PFKL, GAPDH, PKM2, LDHA), switching metabolism toward aerobic glycolysis [#1]. ME2-derived pyruvate also stabilizes \\u03b2-catenin to promote migration and invasion [#7]. A homozygous frameshift variant producing truncated, unstable ME2 protein causes a human neurodevelopmental disorder, and the growth arrest of yeast lacking the ME2 ortholog is rescued by human ME2, establishing an essential mitochondrial role [#11]. The enzyme is allosterically druggable at a site distinct from the active site (embonic acid) and by active-site-directed inhibitors (NPD389) [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Before molecular characterization, the question was simply where ME2 resides in the genome; linkage mapping anchored the locus, providing the genetic foothold for later study.\",\n      \"evidence\": \"Family-based genetic linkage analysis placing ME2 on chromosome 6p near F13A\",\n      \"pmids\": [\"2860058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chromosomal assignment only, no molecular or functional mechanism\", \"No protein-level characterization\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"It was unclear how mitochondrial ME2 differs functionally from its paralogs; kinetic profiling established ME2 as a dual-cofactor, fumarate-activated, ATP-inhibited enzyme distinct from ME1 and ME3.\",\n      \"evidence\": \"Spectrophotometric enzyme activity and immunoblotting across human, rat, mouse islets and INS-1 cells\",\n      \"pmids\": [\"19691144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for cofactor promiscuity or allosteric regulation\", \"Physiological role in islets not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether ME2 could be pharmacologically targeted and at what site was unknown; embonic acid was shown to allosterically inhibit ME2 at the fumarate site/dimer interface, distinct from the catalytic site, and induce p53-independent senescence.\",\n      \"evidence\": \"In vitro enzymatic inhibition, mutagenesis, thermal shift binding, shRNA knockdown and senescence assays in H1299 cells\",\n      \"pmids\": [\"26008970\", \"24681895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity over ME1/ME3 not fully established\", \"Off-target cellular effects of allosteric inhibition unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The first activating PTM regulation of ME2 was unknown; SIRT5 desuccinylation at K346 was identified as a nutrient-gated activation switch coupling glutamine availability to mitochondrial respiration.\",\n      \"evidence\": \"Reciprocal Co-IP, K346 mutagenesis, enzymatic and respiration assays, in vitro/in vivo cancer models\",\n      \"pmids\": [\"38007551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Succinyltransferase 'writer' not identified\", \"Stoichiometry of K346 succinylation in vivo unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How ME2 enzymatic output feeds cellular signaling and survival was open; loss-of-function studies showed ME2 supplies pyruvate that stabilizes \\u03b2-catenin to drive migration, and sustains OXPHOS/NADPH to suppress ROS and apoptosis.\",\n      \"evidence\": \"Knockdown/overexpression with pyruvate rescue, \\u03b2-catenin assays; shRNA silencing and allosteric inhibitor with metabolite readouts and AML xenografts\",\n      \"pmids\": [\"37110198\", \"37079187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of pyruvate\\u2013\\u03b2-catenin interaction not structurally defined\", \"Tissue specificity of metabolic vulnerability unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether ME2 has a moonlighting non-catalytic function was unknown; AKT1 phosphorylation at S9 was shown to block mitochondrial import and repurpose cytoplasmic ME2fl as a glycolytic-enzyme scaffold, defining a metabolic switch toward aerobic glycolysis.\",\n      \"evidence\": \"Co-IP, S9 mutagenesis, subcellular fractionation, glycolytic flux assays, in vivo tumor models\",\n      \"pmids\": [\"38263319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the glycolytic scaffold assembly not resolved\", \"Relative abundance of ME2fl scaffold vs mitochondrial pool not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether arginine methylation regulates ME2 and disease relevance of ME2 loss were open; PRMT1 methylation was shown to activate ME2 in HCC, and a human frameshift variant plus yeast complementation established ME2 as essential for mitochondrial function and linked to neurodevelopmental disease.\",\n      \"evidence\": \"Co-IP and mutagenesis with respiration/proliferation assays (PRMT1); whole exome sequencing, truncated protein expression, yeast deletion/rescue\",\n      \"pmids\": [\"39528487\", \"39401966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exact methylated residue(s) not definitively mapped\", \"Single patient; genotype-phenotype spectrum unknown\", \"Mechanism connecting ME2 deficiency to neurodevelopment unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How ME2 activity is coupled to chemoresistance was unknown; ACAT1 acetylation at K156 was shown to activate ME2 under low glucose, driving lactate-dependent protein lactylation that supports homologous recombination repair.\",\n      \"evidence\": \"Co-IP, K156 mutagenesis, enzymatic/glucose-uptake assays, metabolomics, in vitro/in vivo chemoresistance models\",\n      \"pmids\": [\"39951294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lactylation targets in HR repair not enumerated\", \"Interplay between K156, K346 and other PTMs not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"An integrated model of how the multiple activating PTMs (succinylation, acetylation, methylation), AKT1 phosphorylation, and protein-stability control (CYP4F11) are coordinated under specific physiological conditions, and how ME2 dysfunction produces neurodevelopmental disease, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the regulated enzyme or its scaffold form\", \"PTM hierarchy and crosstalk uncharacterized\", \"Mechanistic link between ME2 loss and the neurodevelopmental phenotype not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [6, 0, 2, 3]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6, 1, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 1, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SIRT5\", \"ACAT1\", \"PRMT1\", \"AKT1\", \"PFKL\", \"GAPDH\", \"PKM2\", \"LDHA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}