IDH1 and IDH2: not your typical oncogenes

Abstract

Oncogenes usually increase their normal function when activated. However, seemingly oncogenic mutations in IDH1 and IDH2 reduce their native enzyme activity. In this issue of Cancer Cell, Ward et al. pin down a neomorphic enzyme activity as a possible oncogenic function for these alterations.

Figure 1. Mutations in the active site of IDH1 and IDH2 lead to a neomorphic enzyme activity

Wild-type IDH1 and IDH2 normally catalyze the conversion of isocitrate to α-KG (left reaction), and at the same time reduce NADP+ to NADPH and produce CO₂. R132 in wild-type IDH1, as well as R140 and R172 in wild-type IDH2, form hydrogen bonds with the β-carboxyl (green) of isocitrate. Cancer-derived mutations affecting these residues cause the enzymes to instead convert α-KG to 2HG, while at the same time oxidizing NADPH to NADP⁺ (right reaction). 2HG and isocitrate share an identical chemical backbone but differ solely in the presence of the β-carboxyl on isocitrate, but not 2HG. IDH1 R132, IDH2 R140, and IDH2 R172 mutation apparently favors conversion to 2HG rather than isocitrate since 2HG lacks this group.