2keto4hydroxyglutarate

2-keto-4-hydroxyglutarate (2-KHG) is a five-carbon ketoacid in which a keto group is located at the second carbon and a hydroxy group at the fourth carbon of the glutarate backbone. It is an isomer related to 4-hydroxyglutarate and to the central metabolite α-ketoglutarate (2-oxoglutarate), placing it within the broader family of oxo- and hydroxy-functionalized glutamate derivatives observed in cellular metabolism.

In biological systems, 2-KHG has been detected as a minor or trace metabolite in cells and bodily fluids. Its exact origin in vivo is not fully established; proposed sources include oxidation or rearrangement routes linking 4-hydroxyglutarate metabolism with 2-oxoglutarate pathways. Because it coexists with structurally similar hydroxy- and oxo-glutarate compounds, its production can be linked to enzymes that act on related substrates under varying cellular conditions.

The physiological role of 2-KHG remains unclear. It is not widely recognized as an essential metabolite, and its abundance is generally low under normal conditions. Changes in hydroxyglutarate and oxoglutarate metabolism can influence cellular redox balance and the activity of enzymes that depend on 2-oxoglutarate, but direct causal functions for 2-KHG itself have not been firmly established.

Analytical detection of 2-KHG typically relies on high-sensitivity techniques such as liquid chromatography–mass spectrometry (LC-MS) or nuclear magnetic resonance (NMR) spectroscopy. Distinguishing 2-KHG from closely related isomers requires careful separation and, in some cases, labeling strategies.

See also: alpha-ketoglutarate, 2-hydroxyglutarate, 4-hydroxyglutarate, tricarboxylic acid cycle.