GO:0004591 oxoglutarate dehydrogenase (succinyl-transferring) activity

GO:0004591, oxoglutarate dehydrogenase (succinyl-transferring) activity, is a molecular function that catalyzes the oxidative decarboxylation of 2-oxoglutarate and the subsequent succinylation of a lipoyl-bearing dihydrolipoyllysine residue within the 2-oxoglutarate dehydrogenase complex. This activity is a central component of the Krebs cycle and is essential for the conversion of 2-oxoglutarate to succinyl-CoA, a key metabolite that feeds into the succinyltransferase reaction and downstream energy production. Researchers study this activity to understand how cells balance carbon flux, maintain redox homeostasis, and adapt to metabolic stress. The enzyme is a multienzyme complex composed of E1 (2-oxoglutarate dehydrogenase), E2 (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoyl dehydrogenase) subunits, with the E1 component directly responsible for the succinyl-transferring activity defined by GO:0004591. In bacteria such as Achromobacter aegrifaciens, expression of Krebs cycle enzymes, including 2-oxoglutarate dehydrogenase, is modulated during exochemolithoheterotrophic growth on succinate with thiosulfate as an auxiliary electron donor, highlighting its role in metabolic flexibility. Because this activity sits at the intersection of central metabolism, oxidative stress, and biosynthetic pathways, it is a frequent target in functional genomics and drug discovery. Understanding its regulation and catalytic mechanism is critical for interpreting metabolic phenotypes in cancer, neurodegeneration, and infectious disease models.

GO:0004591 describes the catalytic activity of the E1 subunit of the 2-oxoglutarate dehydrogenase complex. It catalyzes the reaction: N(6)-[(R)-lipoyl]-L-lysyl-[dihydrolipoyllysine-residue succinyltransferase] + 2-oxoglutarate + H+ = N(6)-[(R)-S(8)-succinyldihydrolipoyl]-L-lysyl-[dihydrolipoyllysine-residue succinyltransferase] + CO2. In other words, the enzyme decarboxylates 2-oxoglutarate and transfers a succinyl group to a lipoyl-lysine residue on the dihydrolipoyllysine-residue succinyltransferase, generating a succinyl-dihydrolipoyl intermediate and releasing carbon dioxide.

GO:0004591 is essential for central carbon metabolism because it catalyzes the rate-limiting step that converts 2-oxoglutarate to succinyl-CoA, a metabolite that feeds the Krebs cycle and supports biosynthesis, redox balance, and energy production. Its activity is dynamically regulated during bacterial growth on alternative carbon sources, as shown in Achromobacter aegrifaciens during exochemolithoheterotrophic growth on succinate with thiosulfate as an auxiliary electron donor. In eukaryotes, the same activity is critical for mitochondrial function, and its dysfunction has been linked to metabolic disorders, cancer, and neurodegeneration. Consequently, researchers use this GO term to annotate gene products, interpret metabolic flux data, and design CRISPR-based models to test causal roles in disease.

The following genes and proteins are directly or functionally associated with GO:0004591 and its regulatory network.

GO:0004591 is regulated at multiple levels, including substrate availability, cofactor supply, and transcriptional control of Krebs cycle enzymes. In Achromobacter aegrifaciens, expression of Krebs cycle enzymes, including 2-oxoglutarate dehydrogenase, is modulated during exochemolithoheterotrophic growth on succinate with thiosulfate as an auxiliary electron donor, indicating that carbon source and electron acceptor availability influence activity. In eukaryotes, the 2-oxoglutarate dehydrogenase complex is allosterically regulated by NADH and ATP, which inhibit activity, and by calcium and ADP, which stimulate it. Post-translational modifications such as phosphorylation and succinylation also modulate enzyme function.

Dysregulation of GO:0004591 alters flux through the Krebs cycle and can promote metabolic reprogramming in cancer cells, including changes in succinyl-CoA levels and mitochondrial respiration. Loss of 2-oxoglutarate dehydrogenase activity has been linked to increased reliance on glutamine and other anaplerotic pathways.

Reduced 2-oxoglutarate dehydrogenase activity is observed in neurodegenerative conditions and is associated with oxidative stress and mitochondrial dysfunction. This makes GO:0004591 a candidate target for neuroprotective strategies.

Mutations affecting the 2-oxoglutarate dehydrogenase complex can lead to metabolic disorders characterized by lactic acidosis and neurological symptoms. Functional studies using CRISPR models help establish causality.

CRISPR-Cas9 knockout of OGDH, DLST, or DLD abolishes or reduces GO:0004591 activity, enabling functional studies of metabolic flux and cell viability. Point-mutation knock-in of catalytic residues allows precise dissection of the succinyl-transfer mechanism.

Stable isotope tracing with 13C-labeled substrates combined with mass spectrometry measures flux through the 2-oxoglutarate dehydrogenase step and identifies compensatory pathways. This approach is often paired with CRISPR models to test causality.

Mass spectrometry-based proteomics can quantify succinylation of DLST and other proteins, linking GO:0004591 activity to global succinylome changes. This is useful for understanding downstream effects of enzyme manipulation.

RNA-seq and promoter-reporter assays measure transcriptional regulation of Krebs cycle genes under different growth conditions, as shown in Achromobacter aegrifaciens during exochemolithoheterotrophic growth. These methods help identify regulatory nodes upstream of GO:0004591.

Researchers studying oxoglutarate dehydrogenase (succinyl-transferring) activity-related genes often need to determine whether a candidate gene is causally involved in metabolic phenotypes, disease progression, or drug response. EDITGENE provides end-to-end CRISPR services to generate precisely engineered cell models that answer these questions.

GO:0004591, oxoglutarate dehydrogenase (succinyl-transferring) activity, is a central molecular function in the Krebs cycle that links 2-oxoglutarate catabolism to succinyl-CoA production and cellular energy metabolism. Its regulation is critical for metabolic flexibility, as demonstrated in bacterial systems during exochemolithoheterotrophic growth. Dysregulation of this activity contributes to cancer, neurodegeneration, and metabolic disorders, making it a high-value target for functional genomics. By combining CRISPR knockout, point-mutation, knock-in, and overexpression models with metabolic and proteomic readouts, researchers can precisely dissect the role of GO:0004591 in health and disease. EDITGENE provides the tools and expertise to accelerate these discoveries.