2hydroxyglutaric

2-hydroxyglutaric is the hydroxy derivative of glutaric acid at the second carbon. In biology it exists as two enantiomers, D-2-hydroxyglutaric acid (D-2-HG) and L-2-hydroxyglutaric acid (L-2-HG), which are not interconvertible and can accumulate under different metabolic conditions. The metabolite is normally present at low levels in body fluids as a minor byproduct of cellular metabolism.

D-2- and L-2-hydroxyglutaric acids can accumulate in humans due to genetic defects or pathological processes. D-2-hydroxyglutaric aciduria is typically caused by deficiencies in the enzyme D2HGDH, leading to elevated D-2-HG levels and a range of neurologic features. L-2-hydroxyglutaric aciduria results from mutations in L2HGDH and presents with neurodevelopmental impairment and progressive leukoencephalopathy. Both conditions are rare and inherited in an autosomal recessive pattern. Diagnosis is usually achieved by quantitative analysis of organic acids in urine or plasma, followed by supportive genetic testing.

In cancer biology, mutations in isocitrate dehydrogenase enzymes (IDH1 or IDH2) can aberrantly convert alpha-ketoglutarate to D-2-hydroxyglutarate, resulting in elevation of this metabolite. D-2-HG acts as an oncometabolite, inhibiting several alpha-ketoglutarate–dependent dioxygenases, which can alter epigenetic regulation and cellular differentiation and contribute to tumor development in certain cancers.

Management of elevated 2-hydroxyglutarate focuses on treating underlying causes and managing symptoms; there is no universal cure for the inherited forms, and research continues into targeted approaches for IDH-mutant cancers and related metabolic disorders.