Open Access2‐Hydoxyglutarate: D/R iving Pathology in g L ioma S
Author(s) -
Wahl Daniel R.,
Venneti Sriram
Publication year - 2015
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12309
Subject(s) - isocitrate dehydrogenase , glioma , cancer research , mutant , carcinogenesis , chemistry , in vivo , methyltransferase , enzyme , methylation , microbiology and biotechnology , biology , biochemistry , dna , genetics , gene
Common pathways and mechanisms can be found in both cancers and inborn errors of metabolism. 2‐Hydroxyglutarate (2‐ HG ) acidurias and isocitrate dehydrogenase ( IDH ) 1/2 mutant tumors are examples of this phenomenon. 2‐ HG can exist in two chiral forms, D (R)‐2‐ HG and L ( S )‐2‐ HG , which are elevated in D ‐ and L ‐acidurias, respectively. D‐2‐ HG was subsequently discovered to be synthesized in IDH 1/2 mutant tumors including ∼70% of intermediate‐grade gliomas and secondary glioblastomas ( GBM ). Recent studies have revealed that L ‐2‐ HG is generated in hypoxia in IDH wild‐type tumors. Both 2‐ HG enantiomers have similar structures as α‐ketoglutarate (α‐ KG ) and can competitively inhibit α‐ KG ‐dependent enzymes. This inhibition modulates numerous cellular processes, including histone and DNA methylation, and can ultimately impact oncogenesis. D ‐2‐ HG can be detected in vivo in glioma patients and animal models using advanced imaging modalities. Finally, pharmacologic inhibitors of mutant IDH 1/2 attenuate the production of D ‐2‐ HG and show great promise as therapeutic agents.