Novel Insight into 2-Hydroxyglutarate Production in Human Cells

Abstract

Mutations in metabolic enzymes, especially Isocitrate dehydrogenase1/2, strongly implicate altered metabolism in tumorigenesis by generating 2-HG. 2-HG is an oncometabolite mostly identified in AML and glioma. Wild type IDH1 and IDH2 catalyze the interconversion of isocitrate and α-KG, which is a TCA cycle intermediate and an essential cofactor for many enzymes, while 2-HG produced by mutant of IDH1/2 functions as a competitive inhibitor of α-KG, leading to epigenetic alteration and disruption of PHDs-mediated protein hydroxylation. However how is 2-HG produced in non-IDH mutated cells is still not well defined. Recent studies demonstrated that the accumulation of 2-HG in non-IDH mutated cells might be due to many other cellular mechanisms, including MYC status, expression of IDH1/2, dysregulation of 2-HGDH and hypoxia. Here we review what is known about the molecular mechanisms of transformation by IDH mutations and the mechanisms of carcinogenic metabolites 2-HG accumulation in non-IDH mutated cells. We also discuss the strategies for separation of two enantiomers of 2-HG (D and L) and their implications for the identification of the cancer subtypes and the development of targeted therapies to treat different types of human malignancies.