D2HGDH, PHYKPL and ME

The gene D2HGDH is hypomethylated in ME patients, and this is associated with quality of life (1). Hypomethylation can result in upregulation of gene transcription. In agreement with this, gene expression of D2HGDH was upregulated in whole blood from adolescent ME/CFS patients (2).

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).

References:

1. Vega et al: Epigenetic modifications and glucocorticoid sensitivity in ME/CFS. BMC Medical Genomics, 2017, 10, 11
2. 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.
3. Lin et al: D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat Comm. 16.jul 2015.
4. Barneda-Zahonero et al: Epigenetic regulation of B lymphocyte differentiation, transdifferentiation and reprogramming. Hindawi, 2012, ID564381
5. Rajagopalan et al. Metabolic plasticity maintains proliferation in pyruvate dehydrogenase deficient cells. Cancer & Metabolism (2015) 3:7