Affinage

OGDH

2-oxoglutarate dehydrogenase complex component E1 · UniProt Q02218

Length
1023 aa
Mass
115.9 kDa
Annotated
2026-04-29
31 papers in source corpus 13 papers cited in narrative 14 extracted findings

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 (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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1989 High

    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

    PMID:2503710

    Open questions at the time
    • Mammalian OGDH gene had not yet been cloned or characterized
    • Regulation in multicellular organisms unknown
    • No disease relevance established
  2. 1994 Medium

    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

    PMID:8020988

    Open questions at the time
    • No functional characterization of human OGDH protein performed
    • Identity and significance of the chromosome 10 locus unresolved
    • Single mapping approach without FISH confirmation
  3. 2016 High

    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

    PMID:27732861

    Open questions at the time
    • Biomarkers for OGDH-dependent versus -independent tumors not clinically validated
    • Direct mechanism linking aspartate anaplerosis to OGDH dependence not fully resolved
  4. 2018 Medium

    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

    PMID:30289354

    Open questions at the time
    • 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
  5. 2019 High

    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

    PMID:31247190

    Open questions at the time
    • Specific succinylation sites on OGDH controlling activity not mapped
    • Whether desuccinylation is the sole SIRT5-dependent mechanism unclear
    • Relevance outside gastric cancer not tested
  6. 2020 High

    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

    PMID:32160276

    Open questions at the time
    • Structural basis for hybrid complex assembly not determined
    • Physiological contexts favoring hybrid versus canonical complex not defined
  7. 2020 High

    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)

    PMID:32383294

    Open questions at the time
    • Neuropathological mechanism (metabolic vs. signaling) not delineated
    • Only one family reported
  8. 2022 High

    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

    PMID:36520152

    Open questions at the time
    • Genotype–phenotype spectrum across variant types not fully characterized
    • No therapeutic rescue strategy tested
  9. 2022 Medium

    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

    PMID:35500439

    Open questions at the time
    • Whether OGDH requirement is specific to primed versus naive pluripotency not tested
    • Single lab study
  10. 2024 High

    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

    PMID:38483541

    Open questions at the time
    • Whether synthetic lethality extends to non-GBM contexts untested
    • Direct target of CPI-613 includes other dehydrogenases, complicating OGDH-specific interpretation
  11. 2025 Medium

    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

    PMID:40571161

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ANGPT2DHTKD1DLDDLSTSIRT5
Complex memberships
alpha-ketoglutarate dehydrogenase complex (OGDHC)hybrid OGDH-DHTKD1 2-oxoadipate dehydrogenase complex

Evidence

Reading pass · 14 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; 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. Gene disruption (kgd1::URA3), enzyme activity assay, lacZ promoter fusion, mRNA northern blot, complementation analysis Molecular and cellular biology High 2503710
1994 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. Somatic cell hybrid panel mapping, genomic localization Genomics Medium 8020988
2016 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. siRNA screen, integrative metabolomics, 3D culture proliferation assay, xenograft tumor growth assay Cell reports High 27732861
2019 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. Co-immunoprecipitation (direct interaction), SIRT5 overexpression/knockdown, OGDH activity assay, succinyl phosphonate inhibitor, siRNA, mitochondrial function assays Experimental cell research High 31247190
2019 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). OGDH overexpression and siRNA knockdown, Western blot, mitochondrial function assays (OCR, ATP, ROS, membrane potential), xenograft tumorigenesis OncoTargets and therapy Medium 31686854
2020 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. Co-immunoprecipitation, DHTKD1/OGDH double knockdown in HEK-293 cells, metabolite quantification (glutarylcarnitine), reconstitution of hybrid complex Human molecular genetics High 32160276
2020 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. Patient fibroblast analysis, HEK293 transfection, Drosophila rescue genetics, enzyme activity assay Journal of inherited metabolic disease High 32383294
2014 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. Targeted proteomics (PRM/SRM mass spectrometry), in silico nitration prediction, Skyline-based quantification Proteomics Medium 25251478
2018 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. OGDH siRNA knockdown, cell-permeable αKG analog (DMKG) add-back, apoptosis assay, autophagy assay, ATG gene expression analysis Cancer biology & therapy Medium 30289354
2022 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. Inducible CRISPRi knockdown, Seahorse mitochondrial stress test, ATP measurement, transcriptome analysis, ETC inhibitor comparison Biochemical and biophysical research communications Medium 35500439
2022 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. Exome sequencing, in silico homology modeling, patient fibroblast protein stability assay, HEK293 transfection, Drosophila rescue genetics, mini-gene splicing assay Genetics in medicine High 36520152
2024 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. 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 JCI insight High 38483541
2025 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. UL82 transfection model, ANGPT2 siRNA, transcriptomic and metabolomic analyses, ubiquitination assay, in vitro and in vivo experiments Tumour virus research Medium 40571161
2025 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. Confocal imaging of nuclear localization, succinyl-proteomics, single-cell nuclei ATAC sequencing, Gln depletion experiments in human and murine MPCs bioRxivpreprint Medium

Source papers

Stage 0 corpus · 31 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 60 30561685
2016 Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH. Cell reports 59 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
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
2019 OGDH promotes the progression of gastric cancer by regulating mitochondrial bioenergetics and Wnt/β-catenin signal pathway. OncoTargets and therapy 26 31686854
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 11 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
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
2025 Circular RNA-OGDH promotes PANoptosis in diabetic cardiomyopathy: A novel mechanistic insight. The Journal of biological chemistry 5 40412523
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
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