GO:0006103 2-oxoglutarate metabolic process: Master Regulator Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0006103 describes the chemical reactions and pathways involving 2-oxoglutarate (alpha-ketoglutarate), a key TCA cycle constituent and central intermediate in amino-acid metabolism.
• 2-Oxoglutarate is a master regulator metabolite that links carbon and nitrogen metabolism and serves as a co-substrate for 2-oxoglutarate-dependent oxygenases.
• 2-Oxoglutarate-dependent dioxygenases act as molecular sensors for cellular oxygen and metabolic status, influencing gene expression and cell fate.
• Dysregulation of 2-oxoglutarate metabolism is implicated in cancer, diabetes, tissue regeneration, and bacterial pathogenesis.
• Key enzymes include isocitrate dehydrogenase (IDH), glutamate dehydrogenase (GLUD), and 2-oxoglutarate dehydrogenase (OGDH), which control flux through this pathway.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable precise interrogation of 2-oxoglutarate metabolic genes in disease and development.
Description
2-Oxoglutarate metabolic process (GO:0006103) encompasses the chemical reactions and pathways involving oxoglutarate, the dianion of 2-oxoglutaric acid. It is a key constituent of the TCA cycle and a key intermediate in amino-acid metabolism. This process is fundamental to cellular energy production, nitrogen balance, and biosynthetic reactions. Beyond its metabolic role, 2-oxoglutarate serves as an essential co-substrate for a large family of 2-oxoglutarate-dependent oxygenases, which regulate diverse biological processes including DNA repair, hypoxia sensing, and epigenetic modifications. Researchers study this pathway because it sits at the intersection of metabolism, signaling, and gene regulation, with profound implications for cancer, diabetes, regeneration, and infectious diseases. Understanding the enzymes, transporters, and regulatory mechanisms of 2-oxoglutarate metabolism provides a foundation for developing targeted therapies and metabolic interventions.
2-oxoglutarate metabolic process At A Glance
| GO ID | GO:0006103 |
|---|---|
| GO term | 2-oxoglutarate metabolic process |
| Ontology | biological_process |
| Synonym | 2-ketoglutarate metabolic process; alpha-ketoglutarate metabolic process; 2-oxoglutarate metabolism |
| Major function | Central metabolic hub in the TCA cycle and amino-acid metabolism; co-substrate for 2-oxoglutarate-dependent oxygenases |
| Key enzymes | Isocitrate dehydrogenase (IDH), glutamate dehydrogenase (GLUD), 2-oxoglutarate dehydrogenase (OGDH) |
| Related metabolites | Glutamate, glutamine, isocitrate, succinyl-CoA, citrate |
| Cellular location | Mitochondrial matrix and cytoplasm |
What Is GO:0006103?
GO:0006103, 2-oxoglutarate metabolic process, is defined as the chemical reactions and pathways involving oxoglutarate, the dianion of 2-oxoglutaric acid. It is a key constituent of the TCA cycle and a key intermediate in amino-acid metabolism. This process includes the synthesis, utilization, and interconversion of 2-oxoglutarate through enzymatic reactions such as oxidative decarboxylation, transamination, and reductive amination.
Why Is 2-oxoglutarate metabolic process Important in Cell Biology?
2-Oxoglutarate metabolic process is critically important because it integrates carbon and nitrogen metabolism, supports energy production, and provides the essential co-substrate for 2-oxoglutarate-dependent dioxygenases that regulate gene expression, DNA repair, and hypoxia responses. Its dysregulation is linked to cancer, diabetes, tissue regeneration, and bacterial infections, making it a prime target for therapeutic intervention and metabolic engineering.
• Central to the TCA cycle and ATP production.
• Serves as a nitrogen shuttle and precursor for glutamate and glutamine synthesis.
• Acts as a co-substrate for 2-oxoglutarate-dependent oxygenases involved in epigenetic regulation and oxygen sensing.
• Modulates cancer cell metabolism and tumor progression through IDH mutations and dioxygenase activity.
• Regulates hepatic gluconeogenesis and systemic glucose homeostasis, with implications for diabetes.
• Influences cell fate decisions during tissue regeneration and heart repair.
• Plays a role in bacterial pathogenesis, including Helicobacter pylori survival.
• Provides a metabolic checkpoint for immune cell function and inflammation.
• Target for metabolic inhibitors and CRISPR-based functional genomics.
• Biomarker potential for metabolic disorders and cancer.
What Happens During 2-oxoglutarate metabolic process?
Production of 2-oxoglutarate in the TCA cycle
In simple terms: 2-Oxoglutarate is made in the mitochondria when isocitrate is converted by isocitrate dehydrogenase.
In the TCA cycle, isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to produce 2-oxoglutarate, generating NADPH and CO2. This reaction is a key control point for flux through the cycle. IDH mutations, common in cancer, can alter the production of 2-oxoglutarate and lead to oncometabolite accumulation.
Interconversion with glutamate and amino acids
In simple terms: 2-Oxoglutarate can be converted to and from glutamate, linking carbon and nitrogen metabolism.
Glutamate dehydrogenase (GLUD) reversibly converts glutamate to 2-oxoglutarate and ammonia, providing a major route for nitrogen assimilation and release. Transaminases also transfer amino groups to 2-oxoglutarate to form glutamate, making it a central nitrogen acceptor. This interconversion is vital for amino-acid metabolism and ammonia detoxification.
Utilization by 2-oxoglutarate-dependent oxygenases
In simple terms: 2-Oxoglutarate is used as a co-substrate by enzymes that modify proteins and DNA, often in response to oxygen.
2-Oxoglutarate-dependent oxygenases (e.g., prolyl hydroxylases, JmjC histone demethylases, TET DNA demethylases) consume 2-oxoglutarate and oxygen to hydroxylate or demethylate substrates, releasing succinate and CO2. These enzymes act as cellular oxygen and metabolic sensors, influencing gene expression, DNA repair, and cell fate. Their activity is directly tied to 2-oxoglutarate availability, linking metabolism to epigenetic regulation.
Oxidative decarboxylation to succinyl-CoA
In simple terms: 2-Oxoglutarate is further broken down by the 2-oxoglutarate dehydrogenase complex to produce energy.
The 2-oxoglutarate dehydrogenase complex (OGDH) catalyzes the oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA and CO2, generating NADH and succinyl-CoA for the TCA cycle. This irreversible step commits 2-oxoglutarate to energy production and is tightly regulated by cellular energy status. Deficiencies in OGDH are associated with metabolic disorders and neurodegeneration.
Regulation of 2-oxoglutarate levels and signaling
In simple terms: Cells adjust 2-oxoglutarate levels to control metabolism and signaling.
2-Oxoglutarate levels are regulated by the balance of production (IDH, GLUD) and consumption (OGDH, dioxygenases). It acts as a signaling molecule that can modulate mTOR activity, autophagy, and cell growth. In diabetes, 2-oxoglutarate supplementation ameliorates hyperglycemia by inhibiting hepatic gluconeogenesis via serpina1e signaling. During tissue regeneration, metabolic adaptations involving 2-oxoglutarate direct cell fate.
Key Genes Involved in GO:0006103 2-oxoglutarate metabolic process
The following genes encode enzymes, transporters, and regulatory proteins directly involved in 2-oxoglutarate metabolic process.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IDH1 | Cytosolic isocitrate dehydrogenase; produces 2-oxoglutarate | Mutations in cancer alter 2-oxoglutarate levels and produce oncometabolite 2-HG |
| IDH2 | Mitochondrial isocitrate dehydrogenase; produces 2-oxoglutarate | Mutations linked to glioma and acute myeloid leukemia |
| IDH3A | Subunit of mitochondrial NAD-dependent IDH complex | TCA cycle flux control; knockout models for metabolic studies |
| GLUD1 | Glutamate dehydrogenase 1; interconverts glutamate and 2-oxoglutarate | Regulates nitrogen metabolism and insulin secretion |
| GLUD2 | Glutamate dehydrogenase 2; brain-specific isoform | Neuronal nitrogen handling and neurotransmission |
| OGDH | 2-Oxoglutarate dehydrogenase complex E1 subunit; converts 2-OG to succinyl-CoA | Deficiency causes metabolic and neurological disorders |
| DLST | Dihydrolipoamide succinyltransferase; OGDH complex component | TCA cycle regulation and energy metabolism |
| DLD | Dihydrolipoamide dehydrogenase; shared E3 subunit of dehydrogenase complexes | Mutations cause E3 deficiency and metabolic disease |
| GOT1 | Glutamic-oxaloacetic transaminase 1; uses 2-OG in transamination | Cytosolic nitrogen shuttling and cancer metabolism |
| GOT2 | Glutamic-oxaloacetic transaminase 2; mitochondrial transaminase | Mitochondrial redox and amino-acid metabolism |
| GPT | Glutamic-pyruvic transaminase; alanine aminotransferase using 2-OG | Liver metabolism and gluconeogenesis |
| KGD4 | 2-Oxoglutarate dehydrogenase complex subunit | Regulates OGDH complex assembly and activity |
| SLC25A11 | Mitochondrial 2-oxoglutarate/malate carrier | Transport of 2-OG across mitochondrial membrane |
| SLC25A1 | Mitochondrial citrate/2-OG carrier | Metabolic flux and cancer metabolism |
| PHD1/EGLN2 | Prolyl hydroxylase using 2-OG; oxygen sensor | Hypoxia signaling and cancer |
| TET2 | DNA demethylase using 2-OG | Epigenetic regulation and leukemia |
| KDM6A | Histone demethylase using 2-OG | Epigenetic control and development |
| MYC | Oncogene regulating glutamine metabolism and 2-OG production | Cancer metabolism and cell growth |
How Is 2-oxoglutarate metabolic process Regulated?
2-Oxoglutarate metabolic process is regulated at multiple levels. Enzyme activity of IDH, GLUD, and OGDH is controlled by substrate availability, allosteric effectors (e.g., NADH, ATP, ADP), and post-translational modifications. The expression of these enzymes is influenced by oncogenes such as MYC and hypoxia-inducible factors (HIFs), which alter flux through the pathway. Additionally, 2-oxoglutarate levels modulate the activity of 2-oxoglutarate-dependent dioxygenases, which in turn regulate gene expression and cellular responses to oxygen and nutrients. In diabetes, 2-oxoglutarate signaling via serpina1e inhibits gluconeogenesis, highlighting endocrine regulation. During tissue regeneration, metabolic adaptations direct cell fate through 2-oxoglutarate-dependent mechanisms.
2-oxoglutarate metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IDH1 | Glioma, acute myeloid leukemia | Knock-in of IDH1 R132H mutation in cell lines |
| IDH2 | Acute myeloid leukemia, glioma | Knockout and point-mutation models |
| GLUD1 | Hyperinsulinism/hyperammonemia syndrome | Knockout mouse models |
| OGDH | Neurodegeneration, metabolic disorders | Conditional knockout in neurons |
| TET2 | Leukemia, myelodysplastic syndromes | Knockout and overexpression cell models |
Cancer
Mutations in IDH1 and IDH2 alter 2-oxoglutarate metabolism, leading to the production of the oncometabolite 2-hydroxyglutarate, which inhibits 2-oxoglutarate-dependent dioxygenases and promotes tumorigenesis. 2-Oxoglutarate-dependent dioxygenases are also involved in DNA repair and epigenetic regulation, and their dysregulation contributes to cancer progression. Targeting 2-oxoglutarate metabolism is a promising therapeutic strategy in gliomas, leukemias, and other cancers.
Diabetes and metabolic disorders
2-Oxoglutarate ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling. Dysregulation of 2-oxoglutarate metabolism is linked to insulin resistance and metabolic syndrome. Enzymes such as GLUD1 and GPT play key roles in nitrogen and glucose homeostasis, making them potential targets for antidiabetic therapies.
Tissue regeneration and cardiovascular disease
Inhibition of fatty acid oxidation enables heart regeneration in adult mice by promoting cardiomyocyte proliferation, a process that involves metabolic shifts including 2-oxoglutarate metabolism. Metabolic adaptations direct cell fate during tissue regeneration, with 2-oxoglutarate serving as a key regulator. These findings suggest that modulating 2-oxoglutarate metabolism could enhance regenerative therapies.
Infectious diseases
2-Oxoglutarate:acceptor oxidoreductase-catalyzed redox cycling effectively targets coccoid forms of Helicobacter pylori, highlighting the importance of 2-oxoglutarate metabolism in bacterial pathogenesis. This pathway is essential for H. pylori survival and could be exploited for antimicrobial development.
From 2-oxoglutarate metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of IDH1 affect 2-oxoglutarate levels and cell growth? | CRISPR knockout of IDH1 in cancer cell lines |
| Does mutant IDH1 produce 2-hydroxyglutarate? | Knock-in of IDH1 R132H point mutation |
| Can 2-oxoglutarate supplementation rescue metabolic defects? | Overexpression of GLUD1 or IDH2 in metabolic cell models |
| How does OGDH deficiency impact mitochondrial function? | Conditional knockout of OGDH in mouse models |
| Does TET2 loss alter DNA methylation? | Knockout of TET2 in hematopoietic stem cells |
| Can 2-oxoglutarate metabolism be targeted in H. pylori? | Knockout of 2-oxoglutarate:acceptor oxidoreductase in bacterial models |
How to Study the 2-oxoglutarate metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Levels of 2-oxoglutarate, glutamate, succinate, 2-HG | Quantifying metabolic changes in CRISPR models |
| 13C isotope tracing | Flux through TCA cycle and amino-acid pathways | Assessing metabolic rewiring in cancer cells |
| CRISPR knockout screens | Gene essentiality and synthetic lethality | Identifying metabolic vulnerabilities |
| Enzyme activity assay | IDH, GLUD, OGDH, dioxygenase activity | Validating mutant enzymes and inhibitors |
| RNA-seq | Transcriptional changes | Evaluating gene expression after metabolic perturbation |
| ChIP-seq | Histone modifications and DNA methylation | Assessing dioxygenase activity |
| Seahorse respirometry | Mitochondrial respiration and glycolysis | Measuring metabolic phenotype in knockout cells |
| Western blot | Protein expression and post-translational modifications | Confirming knockout or overexpression |
Metabolomics and flux analysis
Mass spectrometry-based metabolomics quantifies 2-oxoglutarate and related metabolites (glutamate, succinate, 2-hydroxyglutarate) in cells and tissues. Isotope tracing with 13C-labeled substrates reveals flux through the TCA cycle and amino-acid metabolism. These methods are essential for validating CRISPR models and assessing metabolic interventions.
CRISPR screening and functional genomics
Genome-wide CRISPR knockout screens identify genes required for 2-oxoglutarate metabolism and cell fitness under metabolic stress. Focused libraries targeting metabolic enzymes can uncover synthetic lethal interactions. Bioinformatics analysis of screening data prioritizes candidate genes for further study.
Enzyme activity assays
In vitro assays measure the activity of IDH, GLUD, OGDH, and 2-oxoglutarate-dependent dioxygenases using purified proteins or cell lysates. These assays help determine the impact of mutations or inhibitors on enzyme function. Coupled reactions with NAD(P)H or succinate production are commonly used.
Gene expression and epigenetic profiling
RNA-seq and ChIP-seq assess transcriptional and epigenetic changes driven by 2-oxoglutarate-dependent dioxygenases. DNA methylation arrays and histone modification ChIP-seq measure the activity of TET and JmjC enzymes. These methods link 2-oxoglutarate metabolism to gene regulation.
How CRISPR Can Be Used to Study GO:0006103 2-oxoglutarate metabolic process
Knockout
CRISPR knockout of genes such as IDH1, IDH2, GLUD1, or OGDH enables researchers to study loss-of-function phenotypes in 2-oxoglutarate metabolism. Knockout cell models reveal effects on metabolite levels, cell growth, and sensitivity to metabolic inhibitors. These models are essential for target validation in cancer and metabolic diseases.
Point Mutation
Point mutations such as IDH1 R132H or IDH2 R140Q are introduced via CRISPR knock-in to model cancer-associated mutations. These models produce 2-hydroxyglutarate and alter 2-oxoglutarate-dependent dioxygenase activity, mimicking human disease. They are valuable for testing targeted therapies.
Knock-in
Knock-in of tagged or reporter alleles (e.g., GFP-IDH1) allows real-time tracking of protein localization and dynamics. Knock-in of disease-relevant mutations in OGDH or GLUD1 provides models for metabolic disorders. These precise edits facilitate mechanistic studies.
Overexpression
Overexpression of IDH2, GLUD1, or 2-oxoglutarate transporters increases 2-oxoglutarate levels and can rescue metabolic defects. Overexpression models are used to study gain-of-function effects and to test metabolic interventions. They complement knockout studies for bidirectional analysis.
How EDITGENE Supports 2-oxoglutarate metabolic process Research
Researchers studying 2-oxoglutarate metabolic process-related genes often need to determine whether a candidate gene is causally involved in metabolic regulation, disease progression, or therapeutic response. Precise genetic models are essential to dissect the roles of enzymes such as IDH1, GLUD1, and OGDH. EDITGENE provides end-to-end CRISPR solutions to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for 2-oxoglutarate metabolic process research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GOT2 Knockout HEK293 Cell Line | EDJ-KQ1967 | Human | 2806 | Details Get a Quote |
| TAT Knockout HEK293 Cell Line | EDJ-KQ2159 | Human | 6898 | Details Get a Quote |
| GOT1 Knockout HEK293 Cell Line | EDJ-KQ4751 | Human | 2805 | Details Get a Quote |
| PHYH Knockout HEK293 Cell Line | EDJ-KQ5454 | Human | 5264 | Details Get a Quote |
| ADHFE1 Knockout HEK293 Cell Line | EDJ-KQ9397 | Human | 137872 | Details Get a Quote |
| GPT2 Knockout HEK293 Cell Line | EDJ-KQ10175 | Human | 84706 | Details Get a Quote |
| KGD4 Knockout HEK293 Cell Line | EDJ-KQ10857 | Human | 92259 | Details Get a Quote |
| D2HGDH Knockout HEK293 Cell Line | EDJ-KQ13090 | Human | 728294 | Details Get a Quote |
| L2HGDH Knockout HEK293 Cell Line | EDJ-KQ14021 | Human | 79944 | Details Get a Quote |
| OGDHL Knockout HEK293 Cell Line | EDJ-KQ14554 | Human | 55753 | Details Get a Quote |
| IDH1 Knockout HEK293 Cell Line | EDJ-KQ17797 | Human | 3417 | Details Get a Quote |
| IDH2 Knockout HEK293 Cell Line | EDJ-KQ17826 | Human | 3418 | Details Get a Quote |
| GOT2 Knockout HCT 116 Cell Line | EDJ-KQ21936 | Human | 2806 | Details Get a Quote |
| GOT2 Knockout HeLa Cell Line | EDJ-KQ21937 | Human | 2806 | Details Get a Quote |
| ADHFE1 Knockout HCT 116 Cell Line | EDJ-KQ36045 | Human | 137872 | Details Get a Quote |
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Frequently Asked Questions About 2-oxoglutarate metabolic process
What is 2-oxoglutarate metabolic process?
It is the set of chemical reactions and pathways involving 2-oxoglutarate (alpha-ketoglutarate), a key TCA cycle constituent and intermediate in amino-acid metabolism, defined by GO:0006103.
What genes are involved in 2-oxoglutarate metabolic process?
Key genes include IDH1, IDH2, IDH3A, GLUD1, GLUD2, OGDH, DLST, DLD, GOT1, GOT2, GPT, SLC25A11, and TET2, among others.
What is the role of 2-oxoglutarate in the TCA cycle?
2-Oxoglutarate is produced by isocitrate dehydrogenase and consumed by the 2-oxoglutarate dehydrogenase complex to generate succinyl-CoA and NADH, driving energy production.
How is 2-oxoglutarate linked to cancer?
Mutations in IDH1 and IDH2 alter 2-oxoglutarate metabolism and produce the oncometabolite 2-hydroxyglutarate, which promotes tumorigenesis by inhibiting dioxygenases.
Can 2-oxoglutarate be used to treat diabetes?
Studies in mice show that alpha-ketoglutaric acid ameliorates hyperglycemia by inhibiting hepatic gluconeogenesis via serpina1e signaling.
What are 2-oxoglutarate-dependent dioxygenases?
They are enzymes that use 2-oxoglutarate and oxygen to modify substrates such as proteins and DNA, acting as sensors for oxygen and metabolic status.
How do researchers study 2-oxoglutarate metabolism?
Common methods include LC-MS metabolomics, 13C isotope tracing, CRISPR knockout screens, enzyme activity assays, and RNA-seq.
What CRISPR models are available for 2-oxoglutarate genes?
Knockout, point mutation (e.g., IDH1 R132H), knock-in, and overexpression models can be generated for functional studies.
Is 2-oxoglutarate involved in tissue regeneration?
Yes, metabolic adaptations involving 2-oxoglutarate direct cell fate during tissue regeneration, and inhibiting fatty acid oxidation enables heart regeneration in mice.
What diseases are linked to 2-oxoglutarate metabolic process?
Cancer, diabetes, neurodegenerative disorders, and bacterial infections such as Helicobacter pylori are associated with dysregulation of this pathway.
Conclusion
2-Oxoglutarate metabolic process (GO:0006103) is a central metabolic pathway that bridges energy production, amino-acid metabolism, and epigenetic regulation. Its dysregulation contributes to cancer, diabetes, and infectious diseases, making it a high-priority target for therapeutic development. Advances in CRISPR-based models and metabolomics are accelerating our understanding of this pathway and its role in health and disease. EDITGENE provides comprehensive CRISPR solutions to support mechanistic and translational research on 2-oxoglutarate metabolism.
References
- 1. Islam MS et al.. 2018. 2-Oxoglutarate-Dependent Oxygenases.. Annu Rev Biochem 87:585-620 PMID: 29494239
- 2. Li X et al.. 2023. Inhibition of fatty acid oxidation enables heart regeneration in adult mice.. Nature 622(7983):619-626 PMID: 37758950
- 3. Losman JA et al.. 2020. 2-Oxoglutarate-dependent dioxygenases in cancer.. Nat Rev Cancer 20(12):710-726 PMID: 33087883
- 4. Chaves-Perez A et al.. 2025. Metabolic adaptations direct cell fate during tissue regeneration.. Nature 643(8071):468-477 PMID: 40500453
- 5. Yuan Y et al.. 2022. α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling.. Sci Adv 8(18):eabn2879 PMID: 35507647
- 6. Hang X et al.. 2025. 2-oxoglutarate:acceptor oxidoreductase-catalyzed redox cycling effectively targets coccoid forms of Helicobacter pylori.. Nat Commun 16(1):6965 PMID: 40730563
- 7. Huergo LF et al.. 2015. The Emergence of 2-Oxoglutarate as a Master Regulator Metabolite.. Microbiol Mol Biol Rev 79(4):419-35 PMID: 26424716
- 8. Nakayama K et al.. 2025. [2-oxoglutarate-dependent dioxygenase family as a molecular sensor for cellular oxygen and metabolic sensing].. Nihon Yakurigaku Zasshi 160(4):251-255 PMID: 40603030
