Glutamate and α-ketoglutarate: key players in glioma metabolism

Abstract

Glioblastoma multiforme (GBM), or grade IV astrocytoma, is the most common type of primary brain tumor. It has a devastating prognosis with a 2-year-overall survival rate of only 26 % after standard treatment, which includes surgery, radiation, and adjuvant chemotherapy with temozolomide. Also lower grade gliomas are difficult to treat, because they diffusely spread into the brain, where extensive removal of tissue is critical. Better understanding of the cancer's biology is a key for the development of more effective therapy approaches. The discovery of isocitrate dehydrogenase (IDH) mutations in leukemia and glioma drew attention to specific metabolic aberrations in IDH-mutant gliomas. In the center of the metabolic alterations is α-ketoglutarate (αKG), an intermediate metabolite in the tricarboxylic acid (TCA) cycle, and the associated amino acid glutamate (Glu). This article highlights the role of these metabolites in glioma energy and lipid production and indicates possible weak spots of IDH-mutant and IDH-wt gliomas.

Keywords: Alpha-ketoglutarate; Branched chain amino acids; Glioma; Glutamate; Isocitrate dehydrogenase.

Fig. 1

Glutamate dehydrogenase mediates the NADH-producing conversion of glutamate to α-ketoglutarate. From https://www.david-bender.co.uk (assessed 26-02-2016)

Fig. 2

Intact TCA cycle (green). When PDH is blocked, or the TCA cycle is disrupted for other reasons, IDH-dependent reductive carboxylation sustains the formation of intermediate metabolites and fatty acids (red). From Mullen et al. (2012) with permission

Fig. 3

Overview of biochemical reactions for energy and lipid production in the cell. α-ketoglutarate (αKG) and glutamate (Glu) are in the center of pathways like glutaminolysis or reductive carboxylation. Mutant IDH1 changes the dynamics of metabolic processes in the cell and leads to accumulation of 2HG. 2HG in turn inhibits JHDMs and TET, which leads to a hypermethylated phenotype. Ac-CoA, acetyl-CoA; OAA, oxaloacetate; Gln, glutamine; Glu, glutamate; Cys, cysteine; αKG, α-ketoglutarate; Succ-CoA, succinyl-CoA; Fum, fumarate; Mal, malate; PDH, pyruvate dehydrogenase; ACL, ATP-citrate lyase; IDH, isocitrate dehydrogenase; αKGDH, α-ketoglutarate dehydrogenase; JHDMs, Jumonji domain-containing histone demethylases; TET, Ten-Eleven-Translocation

Fig. 4

In IDH1/2 wild-type cells, continuous NADPH production ensures low ROS levels (left). Mutant IDH1/2 activity consumes NADPH and lowers NADPH production. That results in increased ROS levels (right). ROS reactive oxygen species