{"gene":"OGDH","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1989,"finding":"KGD1 (yeast ortholog of OGDH) encodes the alpha-ketoglutarate dehydrogenase E1 component; disruption of the chromosomal KGD1 gene abolishes alpha-ketoglutarate dehydrogenase activity, and the encoded protein shares 38% identity with E. coli alpha-ketoglutarate dehydrogenase. Transcription of KGD1 is catabolite-repressed and dependent on HAP2/HAP3 transcription factors acting through a promoter element mapped to -354 to -143.","method":"Gene disruption (kgd1::URA3), enzyme activity assay, lacZ promoter fusion, mRNA northern blot, complementation analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (disruption, enzyme assay, promoter mapping) in foundational yeast ortholog study","pmids":["2503710"],"is_preprint":false},{"year":1994,"finding":"The OGDH gene (encoding E1k, the E1 subunit of alpha-ketoglutarate dehydrogenase complex) was mapped to human chromosome 7p13-p11.2 using somatic cell hybrid panels; a second related sequence (possibly a pseudogene) was mapped to chromosome 10.","method":"Somatic cell hybrid panel mapping, genomic localization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct chromosomal mapping by somatic cell hybrid analysis, single study","pmids":["8020988"],"is_preprint":false},{"year":2016,"finding":"OGDH (E1 subunit of the alpha-ketoglutarate dehydrogenase complex) is required for cancer cell proliferation in 3D culture and xenograft tumor growth; differential aspartate utilization via the malate-aspartate shuttle predicts cellular dependence on OGDH, establishing OGDH as a node linking TCA cycle flux and aspartate anaplerosis.","method":"siRNA screen, integrative metabolomics, 3D culture proliferation assay, xenograft tumor growth assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic screen, metabolomics, in vivo xenograft) with mechanistic pathway placement","pmids":["27732861"],"is_preprint":false},{"year":2019,"finding":"SIRT5 directly interacts with OGDH and desuccinylates OGDH, thereby inhibiting OGDH complex activity; this inhibition decreases mitochondrial membrane potential, ATP production, and increases ROS and NADP+/NADPH ratio in gastric cancer cells. OGDH inhibition (by succinyl phosphonate or siRNA) suppresses cell growth and migration caused by SIRT5 deletion.","method":"Co-immunoprecipitation (direct interaction), SIRT5 overexpression/knockdown, OGDH activity assay, succinyl phosphonate inhibitor, siRNA, mitochondrial function assays","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP establishing direct interaction, enzymatic activity assay, multiple functional readouts in same study","pmids":["31247190"],"is_preprint":false},{"year":2019,"finding":"OGDH positively regulates mitochondrial bioenergetics (membrane potential, oxygen consumption rate, ATP production) and activates the Wnt/β-catenin signaling pathway (upregulating β-catenin, slug, TCF8/ZEB1, cyclin D1, MMP9) in gastric cancer cells; modulation of OGDH expression correspondingly affects EMT markers (E-cadherin, N-cadherin, ZO-1, claudin-1).","method":"OGDH overexpression and siRNA knockdown, Western blot, mitochondrial function assays (OCR, ATP, ROS, membrane potential), xenograft tumorigenesis","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD/OE with multiple defined cellular phenotypes but pathway placement is correlative without direct epistasis experiments","pmids":["31686854"],"is_preprint":false},{"year":2020,"finding":"DHTKD1 forms a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex with OGDH, dihydrolipoyl succinyltransferase, and dihydrolipoamide dehydrogenase; OGDH is responsible for remaining glutarylcarnitine production in DHTKD1-deficient cells, demonstrating that 2-oxoadipic acid is also a substrate for OGDH with this hybrid complex displaying improved kinetics towards 2-oxoadipic acid.","method":"Co-immunoprecipitation, DHTKD1/OGDH double knockdown in HEK-293 cells, metabolite quantification (glutarylcarnitine), reconstitution of hybrid complex","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP demonstrating complex formation, functional metabolite readouts, novel substrate identification with kinetic characterization","pmids":["32160276"],"is_preprint":false},{"year":2020,"finding":"A homozygous missense variant p.N320S in OGDH reduces OGDH protein levels and abolishes enzyme activity in patient fibroblasts; expression of mutant OGDH in HEK293 cells produces significantly lower protein than wild-type; Drosophila dOgdh null mutants (lethal) are rescued by wild-type OGDH but not OGDHN320S, and knockdown of dOgdh in the nervous system causes locomotion defects rescued only by wild-type but not mutant Ogdh.","method":"Patient fibroblast analysis, HEK293 transfection, Drosophila rescue genetics, enzyme activity assay","journal":"Journal of inherited metabolic disease","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal systems (human fibroblasts, HEK293, Drosophila in vivo rescue) establishing pathogenic mechanism of specific variant","pmids":["32383294"],"is_preprint":false},{"year":2014,"finding":"OGDH undergoes tyrosine/tryptophan nitration modification in vivo; the degree of nitration on OGDH is higher in myocardial tissue of diabetic mice compared to controls, indicating OGDH is subject to oxidative post-translational modification under diabetic conditions.","method":"Targeted proteomics (PRM/SRM mass spectrometry), in silico nitration prediction, Skyline-based quantification","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 — targeted mass spectrometry with quantitative comparison, but single study without functional consequence of modification","pmids":["25251478"],"is_preprint":false},{"year":2018,"finding":"p53 activation by Nutlin-3a reduces alpha-ketoglutarate (αKG) levels; OGDH knockdown increases endogenous αKG levels, rescues cells from Nutlin-3a-induced apoptosis, and restores autophagy and ATG gene expression, placing OGDH downstream of p53 in a pathway where αKG levels control the autophagy-apoptosis decision.","method":"OGDH siRNA knockdown, cell-permeable αKG analog (DMKG) add-back, apoptosis assay, autophagy assay, ATG gene expression analysis","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (KD + metabolite rescue) with defined cellular phenotype, single lab","pmids":["30289354"],"is_preprint":false},{"year":2022,"finding":"OGDH knockdown by CRISPRi in human embryonic stem cells disrupts TCA cycle metabolites, diminishes mitochondrial respiration activity and total ATP levels, and causes hESC death with aberrant transcriptional program; this phenotype is similar to ETC inhibition by small molecule inhibitors, establishing OGDH as required for mitochondrial respiration and stemness maintenance in primed hESCs.","method":"Inducible CRISPRi knockdown, Seahorse mitochondrial stress test, ATP measurement, transcriptome analysis, ETC inhibitor comparison","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — inducible genetic KD with defined metabolic and cellular phenotypes, pharmacological validation, single lab","pmids":["35500439"],"is_preprint":false},{"year":2022,"finding":"Three novel biallelic homozygous variants in OGDH (p.Pro189Leu, p.Ser297Tyr, p.Arg312Lys/p.Phe264_Arg312del) cause a neurodevelopmental disorder; the p.Ser297Tyr variant increases OGDH protein degradation rate in fibroblasts; p.Pro189Leu and p.Ser297Tyr lower protein levels in HEK293 cells; and Drosophila dOgdh carrying equivalent variants fails to rescue dOgdh null lethality, confirming loss-of-function mechanism.","method":"Exome sequencing, in silico homology modeling, patient fibroblast protein stability assay, HEK293 transfection, Drosophila rescue genetics, mini-gene splicing assay","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal approaches across human cells and Drosophila in vivo, with structural modeling and functional validation","pmids":["36520152"],"is_preprint":false},{"year":2024,"finding":"Loss of OGDH function (by CPI-613) causes energy deprivation-driven integrated stress response, upregulating the BH3-only protein Noxa in an ATF4-dependent manner; Noxa silencing attenuates CPI-613-induced cell death; combined OGDH inhibition and Bcl-xL inhibition is synthetically lethal in GBM patient-derived xenografts and neurosphere cultures.","method":"CRISPR/RNAi library screens, CPI-613 pharmacological inhibition, genetic loss-of-function (ABT263), transcriptome and metabolite screening, ATF4/Noxa genetic epistasis, patient-derived xenograft mouse model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (ATF4/Noxa KD), pharmacological and genetic combination experiments, in vivo xenograft validation","pmids":["38483541"],"is_preprint":false},{"year":2025,"finding":"HCMV UL82 promotes OGDH protein stability in colorectal cancer cells by upregulating ANGPT2, which inhibits ubiquitin-mediated degradation of OGDH (deubiquitination); silencing ANGPT2 reduces OGDH protein levels, establishing UL82/ANGPT2/OGDH as a regulatory axis controlling OGDH protein abundance via the ubiquitin-proteasome pathway.","method":"UL82 transfection model, ANGPT2 siRNA, transcriptomic and metabolomic analyses, ubiquitination assay, in vitro and in vivo experiments","journal":"Tumour virus research","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay establishing post-translational regulatory mechanism, but single study without writer/eraser identified","pmids":["40571161"],"is_preprint":false},{"year":2025,"finding":"Under glutamine deficiency conditions, OGDH relocalizes from mitochondria to the nucleus in muscle progenitor cells; this nuclear OGDH is associated with elevated histone succinylation and restricted chromatin accessibility of the MyoD1 locus, impeding myogenic differentiation.","method":"Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, Gln depletion experiments in human and murine MPCs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by confocal imaging linked to functional epigenetic consequence, but preprint and single lab","pmids":[],"is_preprint":true}],"current_model":"OGDH encodes the rate-limiting E1 (alpha-ketoglutarate dehydrogenase) subunit of the alpha-ketoglutarate dehydrogenase complex (OGDHC), which catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA in the TCA cycle; its activity is post-translationally regulated by SIRT5-mediated desuccinylation and ubiquitin-mediated degradation (stabilized by ANGPT2), it can form a hybrid complex with DHTKD1 to metabolize 2-oxoadipic acid, it controls cellular alpha-KG levels that determine autophagy versus apoptosis downstream of p53, and loss-of-function causes neurological disease and impaired mitochondrial respiration while synthetic lethality with Bcl-xL inhibition occurs upon OGDH loss in glioblastoma."},"narrative":{"teleology":[{"year":1989,"claim":"Identification of KGD1 as the yeast ortholog encoding the E1 subunit of alpha-ketoglutarate dehydrogenase established that a single gene product is both necessary and sufficient for this enzymatic activity, and revealed catabolite repression of its transcription.","evidence":"Gene disruption (kgd1::URA3), enzyme activity assay, lacZ promoter fusion, and northern blot in S. cerevisiae","pmids":["2503710"],"confidence":"High","gaps":["Mammalian OGDH gene had not yet been cloned or characterized","Regulation in multicellular organisms unknown","No disease relevance established"]},{"year":1994,"claim":"Mapping human OGDH to chromosome 7p13-p11.2 anchored the gene in the human genome and identified a second related locus on chromosome 10, later recognized as a potential pseudogene or paralog.","evidence":"Somatic cell hybrid panel mapping","pmids":["8020988"],"confidence":"Medium","gaps":["No functional characterization of human OGDH protein performed","Identity and significance of the chromosome 10 locus unresolved","Single mapping approach without FISH confirmation"]},{"year":2016,"claim":"Demonstration that cancer cell proliferation in 3D culture and xenograft growth depends on OGDH, linked via differential aspartate utilization through the malate-aspartate shuttle, established OGDH as a metabolic vulnerability node in tumors.","evidence":"siRNA screen, integrative metabolomics, 3D culture and xenograft assays in cancer cell lines","pmids":["27732861"],"confidence":"High","gaps":["Biomarkers for OGDH-dependent versus -independent tumors not clinically validated","Direct mechanism linking aspartate anaplerosis to OGDH dependence not fully resolved"]},{"year":2018,"claim":"Placing OGDH downstream of p53 in an alpha-KG–dependent autophagy-to-apoptosis switch revealed a non-canonical signaling role for TCA cycle metabolite levels in cell fate decisions.","evidence":"OGDH siRNA knockdown with cell-permeable alpha-KG analog rescue, apoptosis and autophagy assays upon Nutlin-3a treatment","pmids":["30289354"],"confidence":"Medium","gaps":["Direct transcriptional or post-translational mechanism by which p53 modulates OGDH activity not identified","Single lab finding","Alpha-KG sensing mechanism in this context not defined"]},{"year":2019,"claim":"Discovery that SIRT5 directly binds and desuccinylates OGDH to inhibit complex activity established the first specific post-translational regulatory mechanism controlling OGDH enzymatic output and linked it to mitochondrial bioenergetic parameters.","evidence":"Reciprocal co-immunoprecipitation, SIRT5 overexpression/knockdown, OGDH activity assay, and succinyl phosphonate inhibitor in gastric cancer cells","pmids":["31247190"],"confidence":"High","gaps":["Specific succinylation sites on OGDH controlling activity not mapped","Whether desuccinylation is the sole SIRT5-dependent mechanism unclear","Relevance outside gastric cancer not tested"]},{"year":2020,"claim":"Identification of a hybrid OGDH-DHTKD1 complex that decarboxylates 2-oxoadipic acid expanded OGDH's substrate repertoire beyond alpha-ketoglutarate and explained residual glutarylcarnitine production in DHTKD1-deficient cells.","evidence":"Co-immunoprecipitation, DHTKD1/OGDH double knockdown in HEK-293, metabolite quantification, and reconstitution of the hybrid complex with kinetic characterization","pmids":["32160276"],"confidence":"High","gaps":["Structural basis for hybrid complex assembly not determined","Physiological contexts favoring hybrid versus canonical complex not defined"]},{"year":2020,"claim":"A homozygous p.N320S variant in OGDH was shown to abolish enzyme activity and reduce protein levels, and fail to rescue Drosophila dOgdh null lethality and neuronal locomotion defects, establishing the first direct link between OGDH loss-of-function and neurological disease.","evidence":"Patient fibroblast enzyme and protein analysis, HEK293 transfection, Drosophila rescue genetics (null lethality and nervous system-specific knockdown)","pmids":["32383294"],"confidence":"High","gaps":["Neuropathological mechanism (metabolic vs. signaling) not delineated","Only one family reported"]},{"year":2022,"claim":"Additional biallelic OGDH variants confirmed as causing neurodevelopmental disease, with accelerated protein degradation demonstrated for at least one variant, solidifying the genotype–phenotype relationship.","evidence":"Exome sequencing in three families, fibroblast protein stability assay, HEK293 expression, Drosophila rescue genetics, mini-gene splicing assay","pmids":["36520152"],"confidence":"High","gaps":["Genotype–phenotype spectrum across variant types not fully characterized","No therapeutic rescue strategy tested"]},{"year":2022,"claim":"CRISPRi knockdown of OGDH in human embryonic stem cells demonstrated that OGDH is required for mitochondrial respiration and maintenance of the primed pluripotent state, extending its essential role to stem cell biology.","evidence":"Inducible CRISPRi, Seahorse metabolic analysis, ATP measurement, transcriptome profiling in hESCs","pmids":["35500439"],"confidence":"Medium","gaps":["Whether OGDH requirement is specific to primed versus naive pluripotency not tested","Single lab study"]},{"year":2024,"claim":"OGDH inhibition was shown to activate an ATF4-dependent integrated stress response that upregulates the BH3-only protein Noxa, creating a therapeutically exploitable synthetic lethality with Bcl-xL inhibition in glioblastoma.","evidence":"CRISPR/RNAi screens, CPI-613 pharmacological inhibition, ATF4/Noxa genetic epistasis, patient-derived xenograft models","pmids":["38483541"],"confidence":"High","gaps":["Whether synthetic lethality extends to non-GBM contexts untested","Direct target of CPI-613 includes other dehydrogenases, complicating OGDH-specific interpretation"]},{"year":2025,"claim":"ANGPT2 was identified as a stabilizer of OGDH protein by inhibiting its ubiquitin-mediated proteasomal degradation, establishing a second post-translational regulatory axis (ubiquitin-dependent) controlling OGDH abundance.","evidence":"ANGPT2 siRNA, ubiquitination assay, UL82 transfection model in colorectal cancer cells","pmids":["40571161"],"confidence":"Medium","gaps":["The specific E3 ubiquitin ligase and deubiquitinase acting on OGDH not identified","Single study in one cancer type","ANGPT2 is a secreted factor — mechanism of its intracellular regulation of OGDH ubiquitination unclear"]},{"year":null,"claim":"Key unresolved questions include the structural basis for OGDH's integration into canonical versus hybrid DHTKD1-containing complexes, the identity of the E3 ligase targeting OGDH for ubiquitin-dependent degradation, the specific succinylation sites that regulate activity, and whether nutrient-stress-induced nuclear relocalization of OGDH has a physiological epigenetic role in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of human OGDHC","E3 ligase for OGDH unknown","Functional consequence of OGDH nuclear relocalization not confirmed in peer-reviewed literature"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,3,5,6]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,4,9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,5,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4,11]}],"complexes":["alpha-ketoglutarate dehydrogenase complex (OGDHC)","hybrid OGDH-DHTKD1 2-oxoadipate dehydrogenase complex"],"partners":["SIRT5","DHTKD1","DLST","DLD","ANGPT2"],"other_free_text":[]},"mechanistic_narrative":"OGDH encodes the E1 (alpha-ketoglutarate dehydrogenase) subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex (OGDHC), which catalyzes the rate-limiting oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA in the tricarboxylic acid cycle and is essential for mitochondrial respiration, ATP production, and cell viability [PMID:2503710, PMID:35500439]. OGDH activity is post-translationally regulated by SIRT5-mediated desuccinylation, which inhibits the complex and reduces mitochondrial membrane potential and ATP output, and by ubiquitin-dependent proteasomal degradation modulated by ANGPT2 [PMID:31247190, PMID:40571161]. Beyond canonical TCA cycle function, OGDH forms a hybrid complex with DHTKD1 to decarboxylate 2-oxoadipic acid, controls intracellular alpha-ketoglutarate levels that determine the p53-dependent switch between autophagy and apoptosis, and its inhibition triggers an ATF4/Noxa-dependent integrated stress response that creates synthetic lethality with Bcl-xL inhibition in glioblastoma [PMID:32160276, PMID:30289354, PMID:38483541]. Biallelic loss-of-function variants in OGDH cause a neurodevelopmental disorder, as demonstrated by patient fibroblast studies and Drosophila rescue genetics [PMID:32383294, PMID:36520152]."},"prefetch_data":{"uniprot":{"accession":"Q02218","full_name":"2-oxoglutarate dehydrogenase complex component E1","aliases":["2-oxoglutarate dehydrogenase, mitochondrial","Alpha-ketoglutarate dehydrogenase","Alpha-KGDH-E1","Thiamine diphosphate (ThDP)-dependent 2-oxoglutarate dehydrogenase"],"length_aa":1023,"mass_kda":115.9,"function":"2-oxoglutarate dehydrogenase (E1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHC) (PubMed:24495017, PubMed:25210035, PubMed:28435050). Participates in the first step, rate limiting for the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) catalyzed by the whole OGDHC (PubMed:24495017, PubMed:25210035, PubMed:28435050). Catalyzes the irreversible decarboxylation of 2-oxoglutarate (alpha-ketoglutarate) via the thiamine diphosphate (ThDP) cofactor and subsequent transfer of the decarboxylated acyl intermediate on an oxidized dihydrolipoyl group that is covalently amidated to the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST) (PubMed:24495017, PubMed:25210035, PubMed:28435050, PubMed:35272141). Plays a key role in the Krebs (citric acid) cycle, which is a common pathway for oxidation of fuel molecules, including carbohydrates, fatty acids, and amino acids (PubMed:25210035). Can catalyze the decarboxylation of 2-oxoadipate in vitro, but at a much lower rate than 2-oxoglutarate (PubMed:28435050). Can also convert 2-keto-4-hydroxyglutarate (KHG) and CoA into malyl-CoA (By similarity). Mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711)","subcellular_location":"Mitochondrion; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q02218/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OGDH","classification":"Not Classified","n_dependent_lines":576,"n_total_lines":1208,"dependency_fraction":0.4768211920529801},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OGDH","total_profiled":1310},"omim":[{"mim_id":"619701","title":"YOON-BELLEN NEURODEVELOPMENTAL SYNDROME; YOBELN","url":"https://www.omim.org/entry/619701"},{"mim_id":"618580","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80; DEE80","url":"https://www.omim.org/entry/618580"},{"mim_id":"617513","title":"OXOGLUTARATE DEHYDROGENASE-LIKE PROTEIN; OGDHL","url":"https://www.omim.org/entry/617513"},{"mim_id":"616184","title":"CLUSTERED MITOCHONDRIA, D. DISCOIDEUM, HOMOLOG OF; CLUH","url":"https://www.omim.org/entry/616184"},{"mim_id":"614984","title":"DEHYDROGENASE E1 AND TRANSKETOLASE DOMAINS-CONTAINING PROTEIN 1; DHTKD1","url":"https://www.omim.org/entry/614984"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":302.2},{"tissue":"skeletal muscle","ntpm":340.6},{"tissue":"tongue","ntpm":349.9}],"url":"https://www.proteinatlas.org/search/OGDH"},"hgnc":{"alias_symbol":["E1k","OGDC-E1","OGDH2","KGD1"],"prev_symbol":[]},"alphafold":{"accession":"Q02218","domains":[{"cath_id":"-","chopping":"57-90","consensus_level":"medium","plddt":89.8244,"start":57,"end":90},{"cath_id":"-","chopping":"119-238","consensus_level":"high","plddt":88.4594,"start":119,"end":238},{"cath_id":"3.40.50.970","chopping":"252-583","consensus_level":"high","plddt":94.7994,"start":252,"end":583},{"cath_id":"3.40.50.12470","chopping":"610-781_831-873","consensus_level":"high","plddt":97.0053,"start":610,"end":873},{"cath_id":"3.40.50.11610","chopping":"885-1013","consensus_level":"high","plddt":96.5633,"start":885,"end":1013}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02218","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02218-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02218-F1-predicted_aligned_error_v6.png","plddt_mean":90.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OGDH","jax_strain_url":"https://www.jax.org/strain/search?query=OGDH"},"sequence":{"accession":"Q02218","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02218.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02218/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02218"}},"corpus_meta":[{"pmid":"2503710","id":"PMC_2503710","title":"Structure and regulation of KGD1, the structural gene for yeast alpha-ketoglutarate dehydrogenase.","date":"1989","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2503710","citation_count":100,"is_preprint":false},{"pmid":"30561685","id":"PMC_30561685","title":"Screening the ToxCast Phase 1, Phase 2, and e1k Chemical Libraries for Inhibitors of Iodothyronine Deiodinases.","date":"2019","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/30561685","citation_count":60,"is_preprint":false},{"pmid":"27732861","id":"PMC_27732861","title":"Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27732861","citation_count":59,"is_preprint":false},{"pmid":"31247190","id":"PMC_31247190","title":"OGDH mediates the inhibition of SIRT5 on cell proliferation and migration of gastric cancer.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31247190","citation_count":42,"is_preprint":false},{"pmid":"32383294","id":"PMC_32383294","title":"A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease.","date":"2020","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/32383294","citation_count":33,"is_preprint":false},{"pmid":"31686854","id":"PMC_31686854","title":"OGDH promotes the progression of gastric cancer by regulating mitochondrial bioenergetics and Wnt/β-catenin signal pathway.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31686854","citation_count":26,"is_preprint":false},{"pmid":"32160276","id":"PMC_32160276","title":"DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32160276","citation_count":26,"is_preprint":false},{"pmid":"4054903","id":"PMC_4054903","title":"Plasma cholinesterase variants. Family studies of the E1k gene.","date":"1985","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/4054903","citation_count":26,"is_preprint":false},{"pmid":"10385636","id":"PMC_10385636","title":"In situ nucleic acid detection of PDC-E2, BCOADC-E2, OGDC-E2, PDC-E1alpha, BCOADC-E1alpha, OGDC-E1, and the E3 binding protein (protein X) in primary biliary cirrhosis.","date":"1999","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/10385636","citation_count":22,"is_preprint":false},{"pmid":"33656581","id":"PMC_33656581","title":"Expanded high-throughput screening and chemotype-enrichment analysis of the phase II: e1k ToxCast library for human sodium-iodide symporter (NIS) inhibition.","date":"2021","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33656581","citation_count":21,"is_preprint":false},{"pmid":"33854374","id":"PMC_33854374","title":"CircRNA circ-OGDH (hsa_circ_0003340) Acts as a ceRNA to Regulate Glutamine Metabolism and Esophageal Squamous Cell Carcinoma Progression by the miR-615-5p/PDX1 Axis.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33854374","citation_count":20,"is_preprint":false},{"pmid":"8014977","id":"PMC_8014977","title":"A PCR based method to determine the Kalow allele of the cholinesterase gene: the E1k allele frequency and its significance in the normal population.","date":"1994","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8014977","citation_count":19,"is_preprint":false},{"pmid":"25251478","id":"PMC_25251478","title":"A novel targeted proteomics method for identification and relative quantitation of difference in nitration degree of OGDH between healthy and diabetic mouse.","date":"2014","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25251478","citation_count":19,"is_preprint":false},{"pmid":"8020988","id":"PMC_8020988","title":"Localization of the gene (OGDH) coding for the E1k component of the alpha-ketoglutarate dehydrogenase complex to chromosome 7p13-p11.2.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8020988","citation_count":17,"is_preprint":false},{"pmid":"34539976","id":"PMC_34539976","title":"Citrate Synthase and OGDH as Potential Biomarkers of Atherosclerosis under Chronic Stress.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34539976","citation_count":14,"is_preprint":false},{"pmid":"30289354","id":"PMC_30289354","title":"Alpha ketoglutarate levels, regulated by p53 and OGDH, determine autophagy and cell fate/apoptosis in response to Nutlin-3a.","date":"2018","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30289354","citation_count":14,"is_preprint":false},{"pmid":"27468871","id":"PMC_27468871","title":"Frameshift mutations of OGDH, PPAT and PCCA genes in gastric and colorectal 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glioblastoma.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38483541","citation_count":10,"is_preprint":false},{"pmid":"3019402","id":"PMC_3019402","title":"Nucleotide specificity of the E2K----E1K transition in (Na+ + K+)-ATPase as probed with tryptic inactivation and fragmentation.","date":"1986","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/3019402","citation_count":10,"is_preprint":false},{"pmid":"16901643","id":"PMC_16901643","title":"Identification and mRNA expression of Ogdh, QP-C, and two predicted genes in the postnatal mouse brain.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/16901643","citation_count":8,"is_preprint":false},{"pmid":"39848017","id":"PMC_39848017","title":"Modified Shenqi Dihuang Decoction inhibits prostate cancer metastasis by disrupting TCA cycle energy metabolism via NF-kB/p65-mediated OGDH regulation.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39848017","citation_count":7,"is_preprint":false},{"pmid":"15459651","id":"PMC_15459651","title":"PCR method based on the ogdH gene for the detection of Salmonella spp. from chicken meat samples.","date":"2004","source":"Journal of microbiology (Seoul, Korea)","url":"https://pubmed.ncbi.nlm.nih.gov/15459651","citation_count":7,"is_preprint":false},{"pmid":"35500439","id":"PMC_35500439","title":"The functional role of OGDH for maintaining mitochondrial respiration and identity of primed human embryonic stem cells.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35500439","citation_count":6,"is_preprint":false},{"pmid":"34527342","id":"PMC_34527342","title":"OGDH is involved in sepsis induced acute lung injury through the MAPK pathway.","date":"2021","source":"Journal of thoracic 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myogenesis","date":"2025-06-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.30.657066","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.28.656673","title":"OGDHL regulates tumor growth, neuroendocrine marker expression, and nucleotide abundance in prostate cancer","date":"2025-06-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656673","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20256,"output_tokens":3728,"usd":0.058344},"stage2":{"model":"claude-opus-4-6","input_tokens":7125,"output_tokens":2925,"usd":0.163125},"total_usd":0.221469,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"KGD1 (yeast ortholog of OGDH) encodes the alpha-ketoglutarate dehydrogenase E1 component; disruption of the chromosomal KGD1 gene abolishes alpha-ketoglutarate dehydrogenase activity, and the encoded protein shares 38% identity with E. coli alpha-ketoglutarate dehydrogenase. Transcription of KGD1 is catabolite-repressed and dependent on HAP2/HAP3 transcription factors acting through a promoter element mapped to -354 to -143.\",\n      \"method\": \"Gene disruption (kgd1::URA3), enzyme activity assay, lacZ promoter fusion, mRNA northern blot, complementation analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (disruption, enzyme assay, promoter mapping) in foundational yeast ortholog study\",\n      \"pmids\": [\"2503710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The OGDH gene (encoding E1k, the E1 subunit of alpha-ketoglutarate dehydrogenase complex) was mapped to human chromosome 7p13-p11.2 using somatic cell hybrid panels; a second related sequence (possibly a pseudogene) was mapped to chromosome 10.\",\n      \"method\": \"Somatic cell hybrid panel mapping, genomic localization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct chromosomal mapping by somatic cell hybrid analysis, single study\",\n      \"pmids\": [\"8020988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"OGDH (E1 subunit of the alpha-ketoglutarate dehydrogenase complex) is required for cancer cell proliferation in 3D culture and xenograft tumor growth; differential aspartate utilization via the malate-aspartate shuttle predicts cellular dependence on OGDH, establishing OGDH as a node linking TCA cycle flux and aspartate anaplerosis.\",\n      \"method\": \"siRNA screen, integrative metabolomics, 3D culture proliferation assay, xenograft tumor growth assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic screen, metabolomics, in vivo xenograft) with mechanistic pathway placement\",\n      \"pmids\": [\"27732861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIRT5 directly interacts with OGDH and desuccinylates OGDH, thereby inhibiting OGDH complex activity; this inhibition decreases mitochondrial membrane potential, ATP production, and increases ROS and NADP+/NADPH ratio in gastric cancer cells. OGDH inhibition (by succinyl phosphonate or siRNA) suppresses cell growth and migration caused by SIRT5 deletion.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction), SIRT5 overexpression/knockdown, OGDH activity assay, succinyl phosphonate inhibitor, siRNA, mitochondrial function assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP establishing direct interaction, enzymatic activity assay, multiple functional readouts in same study\",\n      \"pmids\": [\"31247190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OGDH positively regulates mitochondrial bioenergetics (membrane potential, oxygen consumption rate, ATP production) and activates the Wnt/β-catenin signaling pathway (upregulating β-catenin, slug, TCF8/ZEB1, cyclin D1, MMP9) in gastric cancer cells; modulation of OGDH expression correspondingly affects EMT markers (E-cadherin, N-cadherin, ZO-1, claudin-1).\",\n      \"method\": \"OGDH overexpression and siRNA knockdown, Western blot, mitochondrial function assays (OCR, ATP, ROS, membrane potential), xenograft tumorigenesis\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/OE with multiple defined cellular phenotypes but pathway placement is correlative without direct epistasis experiments\",\n      \"pmids\": [\"31686854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DHTKD1 forms a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex with OGDH, dihydrolipoyl succinyltransferase, and dihydrolipoamide dehydrogenase; OGDH is responsible for remaining glutarylcarnitine production in DHTKD1-deficient cells, demonstrating that 2-oxoadipic acid is also a substrate for OGDH with this hybrid complex displaying improved kinetics towards 2-oxoadipic acid.\",\n      \"method\": \"Co-immunoprecipitation, DHTKD1/OGDH double knockdown in HEK-293 cells, metabolite quantification (glutarylcarnitine), reconstitution of hybrid complex\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP demonstrating complex formation, functional metabolite readouts, novel substrate identification with kinetic characterization\",\n      \"pmids\": [\"32160276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A homozygous missense variant p.N320S in OGDH reduces OGDH protein levels and abolishes enzyme activity in patient fibroblasts; expression of mutant OGDH in HEK293 cells produces significantly lower protein than wild-type; Drosophila dOgdh null mutants (lethal) are rescued by wild-type OGDH but not OGDHN320S, and knockdown of dOgdh in the nervous system causes locomotion defects rescued only by wild-type but not mutant Ogdh.\",\n      \"method\": \"Patient fibroblast analysis, HEK293 transfection, Drosophila rescue genetics, enzyme activity assay\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal systems (human fibroblasts, HEK293, Drosophila in vivo rescue) establishing pathogenic mechanism of specific variant\",\n      \"pmids\": [\"32383294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OGDH undergoes tyrosine/tryptophan nitration modification in vivo; the degree of nitration on OGDH is higher in myocardial tissue of diabetic mice compared to controls, indicating OGDH is subject to oxidative post-translational modification under diabetic conditions.\",\n      \"method\": \"Targeted proteomics (PRM/SRM mass spectrometry), in silico nitration prediction, Skyline-based quantification\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — targeted mass spectrometry with quantitative comparison, but single study without functional consequence of modification\",\n      \"pmids\": [\"25251478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p53 activation by Nutlin-3a reduces alpha-ketoglutarate (αKG) levels; OGDH knockdown increases endogenous αKG levels, rescues cells from Nutlin-3a-induced apoptosis, and restores autophagy and ATG gene expression, placing OGDH downstream of p53 in a pathway where αKG levels control the autophagy-apoptosis decision.\",\n      \"method\": \"OGDH siRNA knockdown, cell-permeable αKG analog (DMKG) add-back, apoptosis assay, autophagy assay, ATG gene expression analysis\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (KD + metabolite rescue) with defined cellular phenotype, single lab\",\n      \"pmids\": [\"30289354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OGDH knockdown by CRISPRi in human embryonic stem cells disrupts TCA cycle metabolites, diminishes mitochondrial respiration activity and total ATP levels, and causes hESC death with aberrant transcriptional program; this phenotype is similar to ETC inhibition by small molecule inhibitors, establishing OGDH as required for mitochondrial respiration and stemness maintenance in primed hESCs.\",\n      \"method\": \"Inducible CRISPRi knockdown, Seahorse mitochondrial stress test, ATP measurement, transcriptome analysis, ETC inhibitor comparison\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inducible genetic KD with defined metabolic and cellular phenotypes, pharmacological validation, single lab\",\n      \"pmids\": [\"35500439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Three novel biallelic homozygous variants in OGDH (p.Pro189Leu, p.Ser297Tyr, p.Arg312Lys/p.Phe264_Arg312del) cause a neurodevelopmental disorder; the p.Ser297Tyr variant increases OGDH protein degradation rate in fibroblasts; p.Pro189Leu and p.Ser297Tyr lower protein levels in HEK293 cells; and Drosophila dOgdh carrying equivalent variants fails to rescue dOgdh null lethality, confirming loss-of-function mechanism.\",\n      \"method\": \"Exome sequencing, in silico homology modeling, patient fibroblast protein stability assay, HEK293 transfection, Drosophila rescue genetics, mini-gene splicing assay\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal approaches across human cells and Drosophila in vivo, with structural modeling and functional validation\",\n      \"pmids\": [\"36520152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of OGDH function (by CPI-613) causes energy deprivation-driven integrated stress response, upregulating the BH3-only protein Noxa in an ATF4-dependent manner; Noxa silencing attenuates CPI-613-induced cell death; combined OGDH inhibition and Bcl-xL inhibition is synthetically lethal in GBM patient-derived xenografts and neurosphere cultures.\",\n      \"method\": \"CRISPR/RNAi library screens, CPI-613 pharmacological inhibition, genetic loss-of-function (ABT263), transcriptome and metabolite screening, ATF4/Noxa genetic epistasis, patient-derived xenograft mouse model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (ATF4/Noxa KD), pharmacological and genetic combination experiments, in vivo xenograft validation\",\n      \"pmids\": [\"38483541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HCMV UL82 promotes OGDH protein stability in colorectal cancer cells by upregulating ANGPT2, which inhibits ubiquitin-mediated degradation of OGDH (deubiquitination); silencing ANGPT2 reduces OGDH protein levels, establishing UL82/ANGPT2/OGDH as a regulatory axis controlling OGDH protein abundance via the ubiquitin-proteasome pathway.\",\n      \"method\": \"UL82 transfection model, ANGPT2 siRNA, transcriptomic and metabolomic analyses, ubiquitination assay, in vitro and in vivo experiments\",\n      \"journal\": \"Tumour virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay establishing post-translational regulatory mechanism, but single study without writer/eraser identified\",\n      \"pmids\": [\"40571161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under glutamine deficiency conditions, OGDH relocalizes from mitochondria to the nucleus in muscle progenitor cells; this nuclear OGDH is associated with elevated histone succinylation and restricted chromatin accessibility of the MyoD1 locus, impeding myogenic differentiation.\",\n      \"method\": \"Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, Gln depletion experiments in human and murine MPCs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by confocal imaging linked to functional epigenetic consequence, but preprint and single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"OGDH encodes the rate-limiting E1 (alpha-ketoglutarate dehydrogenase) subunit of the alpha-ketoglutarate dehydrogenase complex (OGDHC), which catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA in the TCA cycle; its activity is post-translationally regulated by SIRT5-mediated desuccinylation and ubiquitin-mediated degradation (stabilized by ANGPT2), it can form a hybrid complex with DHTKD1 to metabolize 2-oxoadipic acid, it controls cellular alpha-KG levels that determine autophagy versus apoptosis downstream of p53, and loss-of-function causes neurological disease and impaired mitochondrial respiration while synthetic lethality with Bcl-xL inhibition occurs upon OGDH loss in glioblastoma.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OGDH encodes the E1 (alpha-ketoglutarate dehydrogenase) subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex (OGDHC), which catalyzes the rate-limiting oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA in the tricarboxylic acid cycle and is essential for mitochondrial respiration, ATP production, and cell viability [PMID:2503710, PMID:35500439]. OGDH activity is post-translationally regulated by SIRT5-mediated desuccinylation, which inhibits the complex and reduces mitochondrial membrane potential and ATP output, and by ubiquitin-dependent proteasomal degradation modulated by ANGPT2 [PMID:31247190, PMID:40571161]. Beyond canonical TCA cycle function, OGDH forms a hybrid complex with DHTKD1 to decarboxylate 2-oxoadipic acid, controls intracellular alpha-ketoglutarate levels that determine the p53-dependent switch between autophagy and apoptosis, and its inhibition triggers an ATF4/Noxa-dependent integrated stress response that creates synthetic lethality with Bcl-xL inhibition in glioblastoma [PMID:32160276, PMID:30289354, PMID:38483541]. Biallelic loss-of-function variants in OGDH cause a neurodevelopmental disorder, as demonstrated by patient fibroblast studies and Drosophila rescue genetics [PMID:32383294, PMID:36520152].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Identification of KGD1 as the yeast ortholog encoding the E1 subunit of alpha-ketoglutarate dehydrogenase established that a single gene product is both necessary and sufficient for this enzymatic activity, and revealed catabolite repression of its transcription.\",\n      \"evidence\": \"Gene disruption (kgd1::URA3), enzyme activity assay, lacZ promoter fusion, and northern blot in S. cerevisiae\",\n      \"pmids\": [\"2503710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian OGDH gene had not yet been cloned or characterized\", \"Regulation in multicellular organisms unknown\", \"No disease relevance established\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping human OGDH to chromosome 7p13-p11.2 anchored the gene in the human genome and identified a second related locus on chromosome 10, later recognized as a potential pseudogene or paralog.\",\n      \"evidence\": \"Somatic cell hybrid panel mapping\",\n      \"pmids\": [\"8020988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional characterization of human OGDH protein performed\", \"Identity and significance of the chromosome 10 locus unresolved\", \"Single mapping approach without FISH confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that cancer cell proliferation in 3D culture and xenograft growth depends on OGDH, linked via differential aspartate utilization through the malate-aspartate shuttle, established OGDH as a metabolic vulnerability node in tumors.\",\n      \"evidence\": \"siRNA screen, integrative metabolomics, 3D culture and xenograft assays in cancer cell lines\",\n      \"pmids\": [\"27732861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biomarkers for OGDH-dependent versus -independent tumors not clinically validated\", \"Direct mechanism linking aspartate anaplerosis to OGDH dependence not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placing OGDH downstream of p53 in an alpha-KG–dependent autophagy-to-apoptosis switch revealed a non-canonical signaling role for TCA cycle metabolite levels in cell fate decisions.\",\n      \"evidence\": \"OGDH siRNA knockdown with cell-permeable alpha-KG analog rescue, apoptosis and autophagy assays upon Nutlin-3a treatment\",\n      \"pmids\": [\"30289354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional or post-translational mechanism by which p53 modulates OGDH activity not identified\", \"Single lab finding\", \"Alpha-KG sensing mechanism in this context not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that SIRT5 directly binds and desuccinylates OGDH to inhibit complex activity established the first specific post-translational regulatory mechanism controlling OGDH enzymatic output and linked it to mitochondrial bioenergetic parameters.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, SIRT5 overexpression/knockdown, OGDH activity assay, and succinyl phosphonate inhibitor in gastric cancer cells\",\n      \"pmids\": [\"31247190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific succinylation sites on OGDH controlling activity not mapped\", \"Whether desuccinylation is the sole SIRT5-dependent mechanism unclear\", \"Relevance outside gastric cancer not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of a hybrid OGDH-DHTKD1 complex that decarboxylates 2-oxoadipic acid expanded OGDH's substrate repertoire beyond alpha-ketoglutarate and explained residual glutarylcarnitine production in DHTKD1-deficient cells.\",\n      \"evidence\": \"Co-immunoprecipitation, DHTKD1/OGDH double knockdown in HEK-293, metabolite quantification, and reconstitution of the hybrid complex with kinetic characterization\",\n      \"pmids\": [\"32160276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for hybrid complex assembly not determined\", \"Physiological contexts favoring hybrid versus canonical complex not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A homozygous p.N320S variant in OGDH was shown to abolish enzyme activity and reduce protein levels, and fail to rescue Drosophila dOgdh null lethality and neuronal locomotion defects, establishing the first direct link between OGDH loss-of-function and neurological disease.\",\n      \"evidence\": \"Patient fibroblast enzyme and protein analysis, HEK293 transfection, Drosophila rescue genetics (null lethality and nervous system-specific knockdown)\",\n      \"pmids\": [\"32383294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuropathological mechanism (metabolic vs. signaling) not delineated\", \"Only one family reported\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Additional biallelic OGDH variants confirmed as causing neurodevelopmental disease, with accelerated protein degradation demonstrated for at least one variant, solidifying the genotype–phenotype relationship.\",\n      \"evidence\": \"Exome sequencing in three families, fibroblast protein stability assay, HEK293 expression, Drosophila rescue genetics, mini-gene splicing assay\",\n      \"pmids\": [\"36520152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–phenotype spectrum across variant types not fully characterized\", \"No therapeutic rescue strategy tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPRi knockdown of OGDH in human embryonic stem cells demonstrated that OGDH is required for mitochondrial respiration and maintenance of the primed pluripotent state, extending its essential role to stem cell biology.\",\n      \"evidence\": \"Inducible CRISPRi, Seahorse metabolic analysis, ATP measurement, transcriptome profiling in hESCs\",\n      \"pmids\": [\"35500439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OGDH requirement is specific to primed versus naive pluripotency not tested\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"OGDH inhibition was shown to activate an ATF4-dependent integrated stress response that upregulates the BH3-only protein Noxa, creating a therapeutically exploitable synthetic lethality with Bcl-xL inhibition in glioblastoma.\",\n      \"evidence\": \"CRISPR/RNAi screens, CPI-613 pharmacological inhibition, ATF4/Noxa genetic epistasis, patient-derived xenograft models\",\n      \"pmids\": [\"38483541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether synthetic lethality extends to non-GBM contexts untested\", \"Direct target of CPI-613 includes other dehydrogenases, complicating OGDH-specific interpretation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ANGPT2 was identified as a stabilizer of OGDH protein by inhibiting its ubiquitin-mediated proteasomal degradation, establishing a second post-translational regulatory axis (ubiquitin-dependent) controlling OGDH abundance.\",\n      \"evidence\": \"ANGPT2 siRNA, ubiquitination assay, UL82 transfection model in colorectal cancer cells\",\n      \"pmids\": [\"40571161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific E3 ubiquitin ligase and deubiquitinase acting on OGDH not identified\", \"Single study in one cancer type\", \"ANGPT2 is a secreted factor — mechanism of its intracellular regulation of OGDH ubiquitination unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for OGDH's integration into canonical versus hybrid DHTKD1-containing complexes, the identity of the E3 ligase targeting OGDH for ubiquitin-dependent degradation, the specific succinylation sites that regulate activity, and whether nutrient-stress-induced nuclear relocalization of OGDH has a physiological epigenetic role in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of human OGDHC\", \"E3 ligase for OGDH unknown\", \"Functional consequence of OGDH nuclear relocalization not confirmed in peer-reviewed literature\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 3, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 4, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 5, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4, 11]}\n    ],\n    \"complexes\": [\n      \"alpha-ketoglutarate dehydrogenase complex (OGDHC)\",\n      \"hybrid OGDH-DHTKD1 2-oxoadipate dehydrogenase complex\"\n    ],\n    \"partners\": [\n      \"SIRT5\",\n      \"DHTKD1\",\n      \"DLST\",\n      \"DLD\",\n      \"ANGPT2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}