Reactome | IDH2 dimer decarboxylates isocitrate

IDH2 dimer decarboxylates isocitrate

Stable Identifier

R-HSA-450984

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial matrix

Synonyms

D-threo-isocitrate + NADP(+) => 2-oxoglutarate + CO2 + NADPH

ReviewStatus

5/5

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Mitochondrial isocitrate dehydrogenase IDH2 catalyzes the irreversible reaction of isocitrate and NADP+ to form alpha-oxoglutarate (αOG, αKG), CO2, and NADPH (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 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). Also, IDH2 is a major NADPH producer in the mitochondria and thus plays a crucial role in cellular defense against oxidative stress-induced damage (Jo et al., 2001).

Specific mutations in the IDH2, and also the IDH1 gene, lead to dysfunction of its normal catalytic activity, but also to a new ('neomorphic') function where αOG is reduced to D-2-hydroxyglutarate (D2HG). D2HG is an oncometabolite, accumulating considerably in tumors with mutant IDH. While gliomas with mutant IDH1/2 have a better outcome than those with wild-type IDH, mutant IDH can also lead to the rare metabolic disorder D-2-hydroxyglutaric aciduria 2 (D2HGA2; MIM:613657; Kranendijk et al., 2010; reviewed in Alzial et al., 2021).

Literature References

PubMed ID	Title	Journal	Year
18806796	Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle Hartong, DT, Dange, M, McGee, TL, Berson, EL, Dryja, TP, Colman, RF	Nat Genet	2008
11278619	Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase Jo, SH, Son, MK, Koh, HJ, Lee, SM, Song, IH, Kim, YO, Lee, YS, Jeong, KS, Kim, WB, Park, JW, Song, BJ, Huh, TL	J Biol Chem	2001
18914071	Biosynthesis of tricarboxylic acids by carbon dioxide fixation; enzymatic mechanisms Ochoa, S	J Biol Chem	1948
20847235	IDH2 mutations in patients with D-2-hydroxyglutaric aciduria Kranendijk, M, Struys, EA, Van Schaftingen, E, Gibson, KM, Kanhai, WA, van der Knaap, MS, Amiel, J, Buist, NR, Das, AM, de Klerk, JB, Feigenbaum, AS, Grange, DK, Hofstede, FC, Holme, E, Kirk, EP, Korman, SH, Morava, E, Morris, A, Smeitink, J, Sukhai, RN, Vallance, H, Jakobs, C, Salomons, GS	Science	2010
12207025	Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism Ceccarelli, C, Grodsky, NB, Ariyaratne, N, Colman, RF, Bahnson, BJ	J Biol Chem	2002
14832224	Di- and triphosphopyridine nucleotide isocitric dehydrogenases in yeast Kornberg, A, Pricer, WE Jr	J Biol Chem	1951