Isocitrate dehydrogenases in physiology and cancer: biochemical and molecular insight

Abstract

Isocitrate dehydrogenases play important roles in cellular metabolism and cancer. This review will discuss how the roles of isoforms 1 and 2 in normal cell and cancer metabolism are distinct from those of isoform 3. It will also explain why, unlike 1 and 2, mutations in isoform 3 in tumor are not likely to be driver ones. A model explaining two important features of isocitrate dehydrogenases 1 and 2 mutations, their dominant negative effect and their mutual exclusivity, will be provided. The importance of targeting these mutations and the possibility of augmenting such therapy by targeting other cancer-related pathways will also be discussed.

Keywords: AML; Cancer; Dominant negative effect; Driver mutations; Glioma; IDH; Metabolism; Mutual exclusivity; Targeted therapy.

Fig. 1

a The subcellular localization of the three isocitrate dehydrogenase isoforms and their roles in normal cellular metabolism. IDH isocitrate dehydrogenase, 1 pyruvate dehydrogenase, 2 citrate synthase, 3 mitochondrial aconitase, 4 2-ketoglutarate dehydrogenase, 5 succinyl CoA synthetase, 6 succinate dehydrogenase, 7 fumarate hydratase, 8 malate dehydrogenase, 9 cytosolic aconitase, 10 glutaminase, 11 glutamate transaminase. b The roles of wild type and mutant isocitrate dehydrogenases 1 and 2 in cellular metabolism. CT citrate, (D)-2HG (d) 2-hydroxy glutarate, FAs fatty acids, ICT isocitrate, IDH isocitrate dehydrogenase, Mut mutant, PPP pentose phosphate pathway, Wt wild type, 2KG 2-keto glutarate, 1 mitochondrial aconitase, 2 cytosolic aconitase, 3 citrate lyase, 4 glutaminase, 5 glutamate dehydrogenase, 6 glutamate transaminase, 7 2-ketoglutarate dependent dioxygenases. The dotted red line indicates inhibition

Fig. 2

a The three dimer types formed in a cancer cell heterozygous for IDH1 mutation. Mut mutant, Wt wild type. b The model gain of function and dominant negative effect exerted by heterozygous IDH1/2 mutation. (D)-2HG (d) 2-hydroxy glutarate, ICT isocitrate, Mut mutant, Wt wild type, 2KG 2-keto glutarate. The dotted red line indicates inhibition. The crossed black lines indicate loss of enzyme function in both directions

Fig. 3

a The IDH1 dimer type formed in a cancer cell that is homozygous for IDH1 R132 mutation. IDH1 isocitrate dehydrogenase isoform 1, Mut mutant (e.g. IDH1 R132). b The model explains the absence of IDH1 R132 homozygosity in cancer cells. Since only the Mut-Mut homodimer will be produced in the cancer cell that is homozygous for IDH1 R132, no (D)-2HG will be produced and therefore the oncometabolite drive will be lost causing that particular cancer cell to regress and undergo apoptosis. ICT isocitrate, Mut mutant (e.g. IDH1 R132), Wt wild type, 2KG 2-keto glutarate. The dotted red line indicates inhibition. The crossed black lines indicate loss of enzyme function in both directions