Affinage

OGDH

2-oxoglutarate dehydrogenase complex component E1 · UniProt Q02218

Length
1023 aa
Mass
115.9 kDa
Annotated
2026-06-10
34 papers in source corpus 17 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OGDH encodes the E1 (alpha-ketoglutarate dehydrogenase) subunit of the mitochondrial alpha-ketoglutarate dehydrogenase complex, which catalyzes oxidative decarboxylation in the TCA cycle and is essential for mitochondrial respiration, ATP production, redox balance, and cell viability (PMID:2503710, PMID:35500439). Beyond the canonical complex, OGDH assembles with DHTKD1, DLST, and DLD into a hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase complex, allowing it to consume 2-oxoadipic acid and contribute to glutaryl-CoA production when DHTKD1 is absent (PMID:32160276). By consuming alpha-ketoglutarate, OGDH controls the intracellular level of this metabolite, which feeds back on autophagy and apoptosis: OGDH loss raises alpha-ketoglutarate and restores ATG-dependent autophagy downstream of p53 (PMID:30289354), while OGDH inhibition triggers an ATF4-dependent integrated stress response that upregulates the BH3-only protein Noxa, an axis synthetically lethal with Bcl-xL inhibition in glioblastoma (PMID:38483541). OGDH activity is set post-translationally: SIRT5 directly binds and desuccinylates OGDH to inhibit complex activity (PMID:31247190), the protein is nitrated under diabetic/oxidative conditions (PMID:25251478), and its stability is governed by ubiquitin-mediated turnover that is opposed by ANGPT2 (PMID:40571161). Transcriptionally, OGDH is a target of RELA (NF-κB p65), which binds its promoter and sustains TCA-driven energy metabolism and cancer cell migration (PMID:39848017); in yeast the ortholog KGD1 is catabolite-repressed through HAP2/HAP3 (PMID:2503710). OGDH dependency marks a metabolic vulnerability in cancers reliant on the malate-aspartate shuttle and supports proliferation, EMT/Wnt signaling, and tumor growth (PMID:27732861, PMID:31686854). Biallelic loss-of-function variants in OGDH that reduce protein level and enzymatic activity cause a human neurodevelopmental disorder with metabolic abnormalities, established through patient-cell enzymology and cross-species Drosophila rescue (PMID:32383294, PMID:36520152).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1989 High

    Established the identity of the gene as the E1 catalytic subunit of the alpha-ketoglutarate dehydrogenase complex and its transcriptional control, defining the core enzymatic function.

    Evidence Cloning by complementation, chromosomal disruption, and lacZ promoter reporter assays in yeast KGD1, with hap2/hap3 epistasis

    PMID:2503710

    Open questions at the time
    • Yeast ortholog only; human regulatory architecture not addressed
    • Does not resolve subunit stoichiometry of the human complex
  2. 1994 Medium

    Localized the human OGDH gene, providing a genomic anchor for later disease-variant studies.

    Evidence Somatic cell hybrid panel mapping to chromosome 7p13-p11.2

    PMID:8020988

    Open questions at the time
    • No functional or expression data
    • Relationship of the chromosome 10 related sequence to OGDH function unresolved
  3. 2016 High

    Showed OGDH is a selective metabolic dependency in cancer, answering whether a core TCA enzyme can be a context-specific vulnerability.

    Evidence siRNA screen, metabolomics, 3D proliferation and xenograft assays linking OGDH dependency to malate-aspartate shuttle reliance

    PMID:27732861

    Open questions at the time
    • Biomarker basis of dependency beyond aspartate utilization incomplete
    • Does not address whether dependency generalizes outside the tested cancer types
  4. 2018 Medium

    Connected OGDH enzymatic flux to alpha-ketoglutarate-dependent control of autophagy and apoptosis downstream of p53.

    Evidence OGDH siRNA knockdown with cell-permeable alpha-ketoglutarate add-back and autophagy/ATG readouts in Nutlin-3a-treated cells

    PMID:30289354

    Open questions at the time
    • Direct molecular target of alpha-ketoglutarate in autophagy regulation not identified
    • Single lab, single cell context
  5. 2019 High

    Identified SIRT5 desuccinylation as a direct post-translational switch inhibiting OGDH, and tied OGDH metabolic output to mitochondrial function and tumor signaling.

    Evidence Reciprocal Co-IP, succinyl phosphonate inhibition, siRNA epistasis, and metabolic/Wnt-EMT readouts in gastric cancer cells

    PMID:31247190 PMID:31686854

    Open questions at the time
    • Specific succinylated lysine residues not mapped
    • Mechanistic link between OGDH metabolism and Wnt/β-catenin activation undefined
  6. 2020 High

    Defined a hybrid dehydrogenase complex and expanded OGDH substrate specificity, explaining its role in lysine/tryptophan degradation metabolism.

    Evidence Co-IP, mass spectrometry, and DHTKD1/GCDH KO HEK293 models with glutarylcarnitine quantification

    PMID:32160276

    Open questions at the time
    • Stoichiometry and regulation of the hybrid complex unresolved
    • Physiological tissue contexts where the hybrid complex dominates not defined
  7. 2020 High

    Established OGDH loss-of-function variants as the cause of a human disease through enzymology and cross-species rescue.

    Evidence Whole exome sequencing, patient fibroblast enzymatic assays, HEK293 expression, and Drosophila rescue of lethality/locomotion

    PMID:32383294 PMID:36520152

    Open questions at the time
    • Genotype-phenotype correlations across the variant spectrum incomplete
    • Tissue-specific basis of neurodevelopmental phenotype not resolved
  8. 2022 Medium

    Demonstrated that OGDH is essential for mitochondrial respiration and cell identity in human stem cells, generalizing its requirement beyond cancer.

    Evidence Inducible CRISPRi knockdown with metabolic flux, ATP, and RNA-seq analysis in primed hESCs

    PMID:35500439

    Open questions at the time
    • Direct cause of transcriptional aberrations versus secondary metabolic stress not separated
    • Single lab
  9. 2023 Medium

    Revealed viral exploitation of OGDH, with CSFV targeting it for autophagic degradation and OGDH restraining infection via AMPK-mTOR and IRF3-IFN-β signaling.

    Evidence Co-IP of CSFV C protein with OGDH, NDP52/NBR1 interaction studies, autophagy modulators, and knockdown/overexpression

    PMID:37604413

    Open questions at the time
    • Direct E3/receptor wiring of OGDH ubiquitination not fully defined
    • Mechanism linking OGDH levels to IRF3-IFN-β signaling unresolved
  10. 2024 High

    Placed OGDH inhibition upstream of an ATF4-Noxa apoptotic axis exploitable for synthetic lethality, advancing it as a therapeutic node.

    Evidence CPI-613 inhibition plus genetic loss-of-function with ATF4/Noxa epistasis and patient-derived xenograft validation in glioblastoma

    PMID:38483541

    Open questions at the time
    • Specificity of CPI-613 for OGDH versus other dehydrogenases not fully isolated
    • Determinants of which tumors engage the ATF4-Noxa response undefined
  11. 2025 Medium

    Established additional layers of OGDH regulation: transcriptional activation by RELA and post-translational stabilization opposed by ANGPT2.

    Evidence ChIP-qPCR and luciferase reporter for RELA-promoter binding; Co-IP and ANGPT2 knockdown with ubiquitination/stability readouts

    PMID:39848017 PMID:40571161

    Open questions at the time
    • Identity of the E3 ligase mediating OGDH ubiquitination not determined
    • Whether RELA regulation operates in non-cancer tissues unknown
  12. 2026 Medium

    Linked OGDH to antioxidant defense by physical interaction with and activation of catalase and SOD2, mediating protective effects of alpha-ketoglutarate.

    Evidence Co-IP of OGDH with CAT and SOD2, enzymatic activity assays, and knockdown with in vivo follicular development phenotypes in mice

    PMID:41964037

    Open questions at the time
    • Mechanism by which OGDH boosts CAT/SOD2 activity unresolved
    • Single lab, reproductive-tissue context

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether OGDH has a bona fide nuclear, chromatin-modifying function distinct from its mitochondrial enzymatic role remains open.
  • Preprint; not peer-reviewed or independently confirmed
  • No direct mutagenesis isolating a nuclear OGDH function from mitochondrial loss
  • Mechanism of OGDH nuclear translocation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0016740 transferase activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
ANGPT2CATDHTKD1DLDDLSTSIRT5SOD2
Complex memberships
alpha-ketoglutarate dehydrogenase complex (OGDHC)hybrid 2-oxoglutarate/2-oxoadipate dehydrogenase complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 KGD1 (yeast ortholog of OGDH) encodes the alpha-ketoglutarate dehydrogenase (E1) component of the alpha-ketoglutarate dehydrogenase complex; disruption of the chromosomal copy causes deficiency in alpha-ketoglutarate dehydrogenase activity, and the gene is catabolite repressed via HAP2/HAP3 regulatory proteins binding to a promoter element between -354 and -143. Gene cloning by complementation of kgd1 mutants, chromosomal disruption (kgd1::URA3), lacZ fusion reporter assays, testing in hap2/hap3 mutant backgrounds Molecular and cellular biology High 2503710
1993 The ogd1 and kgd1 mutations in yeast, both abolishing 2-oxoglutarate dehydrogenase activity, are allelic (same gene locus), as demonstrated by complementation and meiotic mapping. Complementation assay, allelism test, meiotic mapping Current genetics Medium 8299151
1994 The OGDH gene (encoding E1k, the E1 subunit of alpha-ketoglutarate dehydrogenase complex) was mapped to human chromosome 7p13-p11.2; a second related sequence (possibly a pseudogene) was mapped to chromosome 10. Somatic cell hybrid panel mapping Genomics Medium 8020988
2014 OGDH protein undergoes tyrosine/tryptophan nitration in myocardial tissue, and the degree of nitration is higher in diabetic mice compared to controls, indicating that OGDH is subject to oxidative post-translational modification (nitration) that is elevated under diabetic conditions. Targeted proteomics using parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) mass spectrometry via Skyline-designed methods Proteomics Medium 25251478
2016 OGDH (E1 subunit of the alpha-ketoglutarate dehydrogenase complex) is required for cancer cell proliferation in 3D culture and xenograft tumor growth in a subset of cancer cells that rely on the malate-aspartate shuttle; differential aspartate utilization predicts OGDH dependency. siRNA screen of TCA cycle enzymes, integrative metabolomics, 3D proliferation assays, xenograft tumor growth assays Cell reports High 27732861
2019 SIRT5 directly interacts with OGDH and desuccinylates OGDH, which inhibits OGDH complex activity; OGDH inhibition (by succinyl phosphonate or siRNA) suppresses cell growth and migration induced by SIRT5 deletion, placing OGDH downstream of SIRT5 in gastric cancer cell proliferation and migration. Co-immunoprecipitation, siRNA knockdown, succinyl phosphonate inhibitor treatment, cell growth/migration assays, measurement of mitochondrial membrane potential, ATP, ROS, and NADP+/NADPH ratio Experimental cell research High 31247190
2019 OGDH knockdown in gastric cancer cells decreases mitochondrial membrane potential, oxygen consumption rate, ATP production, and increases ROS and NADP+/NADPH ratio; OGDH overexpression has opposite effects; furthermore, OGDH knockdown reduces Wnt/β-catenin pathway components (β-catenin, slug, TCF8/ZEB1, cyclin D1, MMP9) while overexpression activates this pathway. siRNA knockdown, overexpression, OCR measurement, ATP assay, ROS measurement, Western blotting for EMT and Wnt pathway markers, xenograft tumor model OncoTargets and therapy Medium 31686854
2020 OGDH interacts with DHTKD1, dihydrolipoyl succinyltransferase (DLST), and dihydrolipoamide dehydrogenase (DLD) to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex; OGDH can use 2-oxoadipic acid as a substrate (in addition to 2-oxoglutarate), contributing to glutaryl-CoA production in cells lacking DHTKD1. Co-immunoprecipitation, mass spectrometry, HEK-293 cell genetic models (DHTKD1 KO + GCDH KO), metabolite quantification (glutarylcarnitine) Human molecular genetics High 32160276
2020 Biallelic loss-of-function variants in OGDH (p.N320S) reduce OGDH protein levels and enzymatic activity in patient fibroblasts and HEK293 cells; expression of mutant OGDH fails to rescue developmental lethality and locomotion defects caused by loss of Drosophila Ogdh, establishing that these variants cause severe loss of OGDH protein function. Whole exome sequencing, patient fibroblast enzymatic assay, HEK293 transfection with WT vs mutant cDNA, Drosophila rescue experiments (lethality and locomotion assays) Journal of inherited metabolic disease High 32383294
2018 OGDH activity regulates intracellular alpha-ketoglutarate (αKG) levels; OGDH knockdown increases endogenous αKG levels and rescues cells from p53 activator Nutlin-3a-induced apoptosis by restoring autophagy and ATG gene expression, placing OGDH downstream of p53 in the regulation of αKG-dependent autophagy and apoptosis. OGDH siRNA knockdown, cell-permeable αKG analog (DMKG) add-back, autophagy assays, ATG gene expression analysis in Nutlin-3a-treated cells Cancer biology & therapy Medium 30289354
2022 Novel homozygous missense variants in OGDH (p.Pro189Leu and p.Ser297Tyr) cause accelerated protein degradation and reduced protein levels; expression in HEK293 cells shows lower protein levels than WT, and neither variant rescues developmental lethality of Drosophila Ogdh null mutants, confirming these are loss-of-function variants. Exome sequencing, in silico homology modeling, protein stability assays in patient fibroblasts and HEK293 cells, Drosophila rescue experiments, mini-gene splicing assay for a splice-site variant Genetics in medicine High 36520152
2022 OGDH knockdown in human embryonic stem cells (hESCs) via inducible CRISPRi disrupts the TCA cycle, diminishes mitochondrial respiration activity, reduces total ATP levels, and leads to cell death and aberrant transcriptional programs, establishing OGDH as essential for mitochondrial respiration and identity maintenance in primed hESCs. CRISPRi-mediated knockdown, metabolic flux analysis, ATP measurement, RNA-seq transcriptomics, pharmacological ETC inhibition for comparison Biochemical and biophysical research communications Medium 35500439
2023 CSFV C protein interacts with OGDH protein; CSFV uses autophagy receptors NDP52/NBR1 to target OGDH for degradation via the autophagy-lysosome pathway, reducing OGDH levels and promoting α-KG secretion; OGDH overexpression inhibits CSFV proliferation through modulation of the AMPK-mTOR-autophagy pathway and the IRF3-IFN-β signaling network. Co-immunoprecipitation (CSFV C protein with OGDH), autophagy agonist/inhibitor treatment (rapamycin/3-MA), siRNA knockdown, overexpression experiments, NDP52/NBR1 interaction studies International journal of biological macromolecules Medium 37604413
2024 Loss of OGDH function (via CPI-613) causes energy deprivation that drives an integrated stress response with ATF4-dependent upregulation of the BH3-only protein Noxa; this is synthetically lethal with Bcl-xL inhibition (ABT263) in glioblastoma; silencing Noxa attenuates cell death, placing OGDH inhibition upstream of ATF4-Noxa in an apoptotic pathway. CPI-613 pharmacological inhibition, genetic loss-of-function (siRNA/CRISPR), transcriptome and metabolite screening, ATF4 and Noxa knockdown epistasis experiments, patient-derived xenograft models JCI insight High 38483541
2025 RELA (NF-κB p65) transcriptionally regulates OGDH; ChIP-qPCR and luciferase reporter assays demonstrated that RELA binds the OGDH promoter; RELA knockdown reduces OGDH expression and impairs TCA cycle energy metabolism and cancer cell migration. ChIP-qPCR, luciferase reporter assay, gene editing, migration assays, metabolomics Phytomedicine Medium 39848017
2025 ANGPT2 (upregulated by HCMV UL82) inhibits ubiquitin-mediated degradation of OGDH (deubiquitination), thereby maintaining OGDH protein stability; silencing ANGPT2 reduces OGDH protein levels, demonstrating post-translational regulation of OGDH via ubiquitination. Co-immunoprecipitation, siRNA knockdown of ANGPT2, ubiquitination pathway analysis, in vitro and in vivo proliferation assays Tumour virus research Medium 40571161
2026 OGDH physically interacts with catalase (CAT) and SOD2, and boosts their enzymatic activities; OGDH knockdown impairs AKG's ability to promote follicular development and antioxidative responses, placing OGDH as a mediator of AKG's protective effects through modulation of CAT/SOD2 antioxidant enzymes. Co-immunoprecipitation (OGDH with CAT and SOD2), enzymatic activity assays, OGDH knockdown, follicular development assays in mice Biological research Medium 41964037
2025 Under glutamine deficiency, OGDH shows increased nuclear localization in muscle progenitor cells, accompanied by elevated histone succinylation and restricted chromatin accessibility at the MyoD1 locus, linking OGDH nuclear translocation to epigenetic regulation of myogenesis. Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, proliferation assays bioRxivpreprint Low

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1989 Structure and regulation of KGD1, the structural gene for yeast alpha-ketoglutarate dehydrogenase. Molecular and cellular biology 100 2503710
2019 Screening the ToxCast Phase 1, Phase 2, and e1k Chemical Libraries for Inhibitors of Iodothyronine Deiodinases. Toxicological sciences : an official journal of the Society of Toxicology 61 30561685
2016 Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH. Cell reports 60 27732861
2019 OGDH mediates the inhibition of SIRT5 on cell proliferation and migration of gastric cancer. Experimental cell research 42 31247190
2020 A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease. Journal of inherited metabolic disease 33 32383294
2019 OGDH promotes the progression of gastric cancer by regulating mitochondrial bioenergetics and Wnt/β-catenin signal pathway. OncoTargets and therapy 27 31686854
2020 DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo. Human molecular genetics 26 32160276
1985 Plasma cholinesterase variants. Family studies of the E1k gene. Human heredity 26 4054903
1999 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. Hepatology (Baltimore, Md.) 22 10385636
2021 Expanded high-throughput screening and chemotype-enrichment analysis of the phase II: e1k ToxCast library for human sodium-iodide symporter (NIS) inhibition. Archives of toxicology 21 33656581
2021 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. Cancer management and research 20 33854374
2014 A novel targeted proteomics method for identification and relative quantitation of difference in nitration degree of OGDH between healthy and diabetic mouse. Proteomics 19 25251478
1994 A PCR based method to determine the Kalow allele of the cholinesterase gene: the E1k allele frequency and its significance in the normal population. Journal of medical genetics 19 8014977
1994 Localization of the gene (OGDH) coding for the E1k component of the alpha-ketoglutarate dehydrogenase complex to chromosome 7p13-p11.2. Genomics 17 8020988
2021 Citrate Synthase and OGDH as Potential Biomarkers of Atherosclerosis under Chronic Stress. Oxidative medicine and cellular longevity 14 34539976
2018 Alpha ketoglutarate levels, regulated by p53 and OGDH, determine autophagy and cell fate/apoptosis in response to Nutlin-3a. Cancer biology & therapy 14 30289354
2016 Frameshift mutations of OGDH, PPAT and PCCA genes in gastric and colorectal cancers. Neoplasma 13 27468871
2023 Role of OGDH in Atophagy-IRF3-IFN-β pathway during classical swine fever virus infection. International journal of biological macromolecules 12 37604413
2024 OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma. JCI insight 10 38483541
2022 Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities. Genetics in medicine : official journal of the American College of Medical Genetics 10 36520152
1986 Nucleotide specificity of the E2K----E1K transition in (Na+ + K+)-ATPase as probed with tryptic inactivation and fragmentation. Biochimica et biophysica acta 10 3019402
2006 Identification and mRNA expression of Ogdh, QP-C, and two predicted genes in the postnatal mouse brain. Neuroscience letters 8 16901643
2025 Modified Shenqi Dihuang Decoction inhibits prostate cancer metastasis by disrupting TCA cycle energy metabolism via NF-kB/p65-mediated OGDH regulation. Phytomedicine : international journal of phytotherapy and phytopharmacology 7 39848017
2004 PCR method based on the ogdH gene for the detection of Salmonella spp. from chicken meat samples. Journal of microbiology (Seoul, Korea) 7 15459651
2025 Circular RNA-OGDH promotes PANoptosis in diabetic cardiomyopathy: A novel mechanistic insight. The Journal of biological chemistry 6 40412523
2022 The functional role of OGDH for maintaining mitochondrial respiration and identity of primed human embryonic stem cells. Biochemical and biophysical research communications 6 35500439
2021 OGDH is involved in sepsis induced acute lung injury through the MAPK pathway. Journal of thoracic disease 6 34527342
1993 The ogd1 and kgd1 mutants lacking 2-oxoglutarate dehydrogenase activity in yeast are allelic and can be differentiated by the cloned amber suppressor. Current genetics 3 8299151
2026 OGDH mediates α-ketoglutarate-induced follicular development and antioxidative response by interacting with CAT/SOD2. Biological research 0 41964037
2026 Simultaneous Inhibition of ACLY and OGDH Has a Synergistic Effect on Hepatocellular Carcinoma Cell Lines. bioRxiv : the preprint server for biology 0 42079189
2026 OGDH primes macrophage for M1-like polarization and ferroptosis in sepsis associated acute lung injury. Respiratory research 0 42143323
2025 Human cytomegalovirus UL82 promotes colorectal cancer cell proliferation through inhibiting the ubiquitination of OGDH via ANGPT2. Tumour virus research 0 40571161
2025 ACO1 OGDH axis drives mitochondrial immune crosstalk in preeclampsia through systems biology enabling dual target therapy. Scientific reports 0 40887492
2025 E1K, a disease-modifying drug candidate for knee osteoarthritis, alleviates pain and regenerates cartilage simultaneously by inhibiting TGF-β1-mediated SMAD1/5/9 signaling in osteoarthritis models. Osteoarthritis and cartilage 0 41317892

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