D2HGDH encodes D-2-hydroxy-glutarate dehydrogenase, which converts D-2-hydroxyglutarate to alpha-ketoglutarate (alpha - KG). Mutations in D2HGDH are present in D-2-hydroxyglutaric aciduria, a rare neurometabolic disorder.
It is possible that 2-hydroxy glutarate is generated in relation to lysine breakdown. PHYKPL, 5-phosphohydroxy-L-lysine phospholyase, gene expression is upregulated in ME/CFS patients (2).
D2HGDH regulates alpha-KG levels and alpha-KG dependent dioxygenase function by modulating isocitrate dehydrogenase 2 (IDH2) (3).
Some of the enzymes that regulate histone and DNA methylation belong to the family of alpha-KG dependent dioxygenases.
Fx, D2HGHD induces demethylation of histone H3K4me3, so it becomes H3K4. This change is relevant to B cell differentiation (3,4)
D2HGDH is one of the genes that when mutant may promote epigenetic changes in B-cell cancer (3).
Furthermore, alpha-KG metabolism and IDH2 expression are part of the metabolic reprogramming-response in pyruvate dehydrogenase deficient cells (5).
- Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
- Nguyen et al: Whole blood gene expression in adolescent CFS: an exploratory crosssectional study suggesting altered B cell differentiation and survival. J Transl Med. 2017,15,102.
- Lin et al: D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat Comm. 16.jul 2015.
- Barneda-Zahonero et al: Epigenetic regulation of B lymphocyte differentiation, transdifferentiation and reprogramming. Hindawi, 2012, ID564381
- Rajagopalan et al. Metabolic plasticity maintains proliferation in pyruvate dehydrogenase deficient cells. Cancer & Metabolism (2015) 3:7