2OG

2-oxoglutarate, commonly abbreviated 2-OG and also known as α-ketoglutarate, is a five-carbon dicarboxylic acid that serves as a central intermediate in the citric acid cycle. It is produced from isocitrate by isocitrate dehydrogenase and is subsequently converted to succinyl-CoA by the α-ketoglutarate dehydrogenase complex, generating NADH in the process.

Beyond its role in energy metabolism, 2-OG acts as a key co-substrate for a broad family of enzymes known as 2-oxoglutarate-dependent dioxygenases (2-OGDDs). These enzymes catalyze hydroxylation and demethylation reactions involved in processes such as collagen synthesis, hypoxia signaling via prolyl hydroxylases, and epigenetic regulation through TET family DNA demethylases and JmjC-domain–containing histone demethylases. 2-OGDDs require Fe2+ and ascorbate and are regulated by cellular levels of 2-OG, succinate, and fumarate, which can modulate enzyme activity.

In health and disease, the balance between 2-OG and its related metabolites is clinically relevant. Mutations in isocitrate dehydrogenase (IDH1 or IDH2) can produce the oncometabolite 2-hydroxyglutarate (2-HG) from 2-OG, inhibiting 2-OGDDs and leading to aberrant DNA and histone methylation and impaired cellular differentiation, a feature observed in several cancers. The interplay between 2-OG and 2-HG is a focus of metabolic and epigenetic research.

Cellular localization and metabolism: most 2-OG is generated in mitochondria and can be shuttled to the cytosol. It also intersects amino acid metabolism through transaminases that interconvert glutamate and α-ketoglutarate, linking nitrogen metabolism with the TCA cycle.