Α-Hydroxyglutaric acid

In biology

In humans the compound is formed by a hydroxyacid-oxoacid transhydrogenase whereas in bacteria is formed by a 2-hydroxyglutarate synthase. The compound can be converted to α-ketoglutaric acid through the action of a 2-hydroxyglutarate dehydrogenase which, in humans, are two enzymes called D2HGDH and L2HGDH. Deficiency in either of these two enzymes lead to a disease known as 2-hydroxyglutaric aciduria.

{{anchor|D-2-hydroxyglutarate}}D-2-hydroxyglutarate

Mutations in isocitrate dehydrogenase (IDH1 and IDH2), which frequently occur in glioma and AML, produce D-2-hydroxyglutarate from alpha-ketoglutarate. D-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate, including histone lysine demethylases.{{cite journal | vauthors = Wang YP, Lei QY | title = Metabolic recoding of epigenetics in cancer | journal = Cancer Commun (Lond) | year = 2018 | volume = 38 | issue = 1 | pages = 1–8 | pmid = 29784032

L-2-hydroxyglutarate

On the other hand, L-2-hydroxyglutarate is produced at high levels in low oxygen conditions, including cells of the immune system.

References

References

1. (November 2009). "Monoclonal antibody specific for IDH1 R132H mutation". Acta Neuropathol..
2. (Feb 2015). "WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation". Molecular Cell.
3. (Jun 2010). "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate". Nature.
4. (May 2011). "The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases". EMBO Rep.
5. (Jan 2011). "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases". Cancer Cell.
6. (Feb 2012). "Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation". Nature.
7. (Mar 2014). "Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases". Nat Commun.
8. (Dec 2016). "S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate". Nature.