D2hydroxyglutarate

D-2-hydroxyglutaric acid, commonly abbreviated D-2-HG, is a chiral dicarboxylic acid and one enantiomer of 2-hydroxyglutarate. The two enantiomers, D-2-HG and L-2-HG, are mirror images and can occur separately in biological systems. D-2-HG is typically present only in small amounts under normal conditions but can accumulate to high levels in certain diseases.

Biosynthesis and metabolism: Endogenous production of D-2-HG is normally minimal. In some cancers, somatic mutations in isocitrate dehydrogenase (IDH1 or IDH2) confer a neomorphic activity that converts α-ketoglutarate to D-2-HG, leading to substantial intracellular accumulation. The enzyme D-2-hydroxyglutarate dehydrogenase (D2HGDH) catabolizes D-2-HG back to α-ketoglutarate; disruptions in this pathway, due to genetic mutations or other metabolic defects, can also raise D-2-HG levels. The balance between production and clearance determines the cellular concentration of D-2-HG.

Clinical significance: In oncology, D-2-HG acts as an oncometabolite. Its accumulation inhibits α-ketoglutarate–dependent dioxygenases, contributing to epigenetic alterations and impaired cellular differentiation observed in IDH-mutant tumors such as some gliomas and leukemias. Measurement of D-2-HG levels in tumor tissue or biofluids can aid in diagnosis and monitoring, and therapies that reduce D-2-HG, including IDH inhibitors, are used in the management of IDH-mutant cancers. Inherited disturbances of D-2-HG metabolism can lead to a rare metabolic disorder characterized by elevated D-2-HG in urine and plasma, with variable neurodevelopmental symptoms.

Detection and analysis: D-2-HG is detected and quantified using analytical methods such as liquid chromatography–mass spectrometry or gas chromatography–mass spectrometry, with methods available to distinguish D- from L-2-HG enantiomers.