273947.fig.001
Figure 1: Main domains of the mitochondrial isocitrate dehydrogenase, IDH2.The homodimeric IDH2 of two 413-amino acid subunits; each 47 kDa subunit is schematically illustrated according the solved crystal structure of porcine IDH2 [50]. Residues 142–187 make up two stacked four-stranded antiparallel β-sheets (middle white marble-shaded domain). Mn2+ and isocitrate in the active site are depicted as a blue circle and rod, respectively. Six Arg residues, which provide hydrogen bonds with isocitrate oxygens [50], are not depicted. Arg 83 (R83) interacts by hydrogen bonding with the 3′-OH of the nicotinamide ribose and thus enhances NADP+ affinity [53]. An Arg residue corresponding to human Arg172, which is often mutated in gliomas and AML, is indicated by an asterisk (*). For activity, the glutathionylation of Cys269 [46] (GS–S) must be removed (X) by reactivation aided by glutaredoxin-2 in the presence of reduced glutathionine, and the protein must be deacetylated by SIRT3 [44]. We hypothesize that Lys212, Lys374, and Lys260 (in porcine notation) are the prime candidates for acetylation causing IDH2 inactivation.