Formation of α-hydroxyglutaric acid (α-hydroxyglutarate, aHG) from α-ketoglutarate is catalyzed by several enzymes. Gain-of-function neomorphic activity of mutated isocitrate dehydrogenase 1 (IDH1) or IDH2 leads to accumulation of d-aHG, whereas promiscuous activity of malate dehydrogenase (MDH) and/or lactate dehydrogenase (LDH) results in the accumulation of l-aHG. Mutated isocitrate dehydrogenase (IDH) has been reported in a wide range of tumours, including acute myeloid leukemia (AML), intrahepatic cholangiocarcinoma, breast carcinoma and glioma. Some effect of aHB on cellular metabolism that promote carcinogenesis (hypermethylated state of DNA and histones, induction of pseudohypoxia) are mediated by inhibition of α-ketoglutarate-dependent dioxygenases. Thus, α-hydroxyglutaric acid has been regarded as an “oncometabolite”, the circulating levels of which may provide diagnostic and prognostic information (2).
Assessment of α-hydroxyglutarate status in patients with IDH mutated malignancies.
Patient/subject: No special precaution.
Matrix: Serum or EDTA plasma.
Volume: Minimum volume is 50 µL, but 200 µL is optimal and allows reanalysis.
Preparation and stability: Probably stable.
Reported values: 0.15-2 µmol/L, and may be 10-fold higher in cancer patients with the IDH1/2 mutation(s).
Intraclass correlation coefficient (ICC): na.
1. Midttun, Ø., McCann, A., Aarseth, O., Krokeide, M., Kvalheim, G., Meyer, K., and Ueland, P.M. (2016). Combined measurement of 6 fat-soluble vitamins and 26 water-soluble functional vitamin markers and amino acids in 50 μL of serum or plasma by high-throughput mass spectrometry. Anal Chem 88, 10427-436.
2. Ježek, P. (2020). 2-Hydroxyglutarate in Cancer Cells. Antioxid Redox Signal, 33, 903-926.