Mitochondrial isocitrate dehydrogenase IDH2 catalyzes the irreversible reaction of isocitrate and NADP+ to form alpha ketoglutarate, CO2, and NADPH + H+ (Hartong et al. 2008). The structure of the active human enzyme has not been determined experimentally, but is inferred to be a homodimer with one Mn++ bound to each subunit based on detailed studies of the homologous pig enzyme (Ceccarelli et al. 2002). NADP-specific IDH2 was the first isocitrate dehydrogenase isoenzyme to be characterized in biochemical studies of the mammalian TCA cycle (Ochoa 1948). Later work with yeast revealed the existence of both NADP-specific (IDH2-homologous) and NAD-specific (IDH3-homologous) enzymes and demonstrated the ADP-dependence of the latter (Kornberg and Pricer 1951), consistent with the now widely accepted view that IDH3 mediates the conversion of isocitrate to alpha-ketoglutarate in the TCA cycle. The physiological function of IDH2 is thus unclear. The recent observation that individuals homozygous for IDH3 mutations that sharply reduce its activity do not show symptoms of deficient energy metabolism in most tissues raises the possibility that the IDH2 reaction may play an accessory role in the TCA cycle (Hartong et al. 2008).