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IDH

Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO2. In humans, IDHs exist in three isoforms: IDH1, IDH2, and IDH3. IDH1 and IDH2 use nicotinamide adenine dinucleotide phosphate (NADP+) as a co-factor and function as homodimers. Even though IDH1/2 enzymes catalyze the equivalent isocitrate-to-αKG conversion, their reactions are coupled to NADP+ reduction and are reversible. The oxidative decarboxylation that converts αKG to isocitrate occurs predominantly in hypoxic conditions producing citrate and acetyl-CoA from glutamine and glutamate. This activity is critical to preserving lipids and cholesterol biosynthesis in hypoxic cells. Beyond their role in intermediary metabolism and energy production, IDH enzymes are involved also in redox status regulation. Indeed, NAD(P)+/NAD(P)H cofactors are essential for electron transfer in a plethora of cellular functions. This class of enzymes has received much attention, as mutations of IDH1 and IDH2 genes have been found in several malignancies. IDH1/2 mutations are heterozygous and result in amino acid changes that occur primarily at residue R132 in IDH1 and R140 or R172 in IDH2. The mutant proteins display a new enzymatic activity able to catalyze the NADPH-dependent reduction of αKG to D-2-hydroxyglutarate (D-2HG).

References

1.Bergaggio E,et al. Cancers (Basel). 2019 Apr 19;11(4). pii: E563.

Metabolic Enzyme/Protease

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