Isocitrate DehydrogenaseEdit

Isocitrate dehydrogenase (IDH) refers to a small family of enzymes that catalyze a key oxidative decarboxylation step in cellular metabolism: the conversion of isocitrate to alpha-ketoglutarate with the concomitant production of reducing equivalents. The IDH family includes three distinct enzyme classes with different cofactor specificities, subcellular localizations, and regulatory properties. In normal physiology, IDH enzymes help drive the citric acid cycle Tricarboxylic acid cycle and, in the NADP+-dependent forms, provide reducing power in the form of NADPH for biosynthesis and antioxidant defense. In cancer biology, a subset of mutations in the NADP+-dependent isoforms (IDH1 and IDH2) confer a neomorphic activity that generates the metabolite 2-hydroxyglutarate, setting off epigenetic and differentiation programs that can contribute to oncogenesis. This dual character—central metabolism on one hand and oncogenic signaling on the other—places IDH at the intersection of basic biochemistry and translational medicine 2-hydroxyglutarate]].

Biochemical function and cofactors

• Reaction and cofactors: The canonical reaction depends on the isoform. IDH1 and IDH2 are NADP+-dependent and convert isocitrate to alpha-ketoglutarate while reducing NADP+ to NADPH. IDH3 is NAD+-dependent and participates in the same oxidative decarboxylation step but generates NADH instead of NADPH. The overall stoichiometry for the NADP+-dependent enzymes is isocitrate + NADP+ → alpha-ketoglutarate + CO2 + NADPH, whereas the NAD+-dependent enzyme follows a similar stoichiometry with NAD+. These reactions link energy production to biosynthesis and redox balance in cells NADPH NADP+.
• Subcellular localization: IDH1 operates primarily in the cytosol and associated organelles like peroxisomes, where it supplies NADPH for reductive biosynthesis and ROS detoxification. IDH2 resides in mitochondria, contributing to mitochondrial NADPH pools and redox control. IDH3 operates within mitochondria as part of the tricarboxylic acid cycle, channeling carbon flux from citrate toward alpha-ketoglutarate and energy production via NADH Tricarboxylic acid cycle.
• Regulation and flux: The activity of IDH enzymes integrates with cellular energy status, redox balance, and substrate availability. In the NADPH-producing forms, flux through IDH1/IDH2 helps sustain fatty acid synthesis, cholesterol biosynthesis, and redox defenses through enzymes such as glutathione peroxidases and thioredoxins glutathione.

Isoforms, structure, and cancer-associated mutations

• IDH1: A cytosolic NADP+-dependent enzyme. In cancer, IDH1 frequently harbors hotspot mutations at arginine 132 (e.g., R132H, R132C). These mutations disrupt normal enzymatic activity and endow the enzyme with a neomorphic function that reduces alpha-ketoglutarate to 2-hydroxyglutarate (2-HG) while decreasing NADPH production in some contexts. The accumulation of 2-HG acts as an oncometabolite that perturbs cellular differentiation and epigenetic regulation. The IDH1 mutation landscape is prominently linked to gliomas and cholangiocarcinomas, among others Glioma 2-hydroxyglutarate.
• IDH2: A mitochondrial NADP+-dependent enzyme. IDH2 mutations occur at residues such as R140 and R172 and similarly generate 2-HG. These mutants contribute to oncogenic programs in hematologic malignancies like acute myeloid leukemia (acute myeloid leukemia), and in solid tumors, with implications for prognosis and therapy IDH2.
• IDH3: A heterotetrameric, mitochondrial enzyme that uses NAD+ rather than NADP+. IDH3 provides a canonical step of the TCA cycle and is not typically mutated in cancer in the same way as IDH1/IDH2. Its regulation is closely tied to mitochondrial energy metabolism and the overall flux of carbon through the cycle Tricarboxylic acid cycle.

Biological and clinical significance

• Normal physiology: By converting isocitrate to alpha-ketoglutarate, IDH enzymes link carbon metabolism with the production of reducing equivalents. IDH1/IDH2-generated NADPH supports anabolic processes (lipid and nucleotide synthesis) and antioxidant defenses, helping cells manage oxidative stress. IDH3 contributes to ATP production via the NADH produced in the same step, reinforcing the link between metabolism and energy supply. Alpha-ketoglutarate itself is a central metabolite used in multiple biosynthetic and catabolic pathways and acts as a key cofactor for dioxygenases involved in epigenetic regulation alpha-ketoglutarate.
• Cancer and targeted therapy: Mutations in IDH1/IDH2 that yield 2-HG production define a distinct molecular subset of cancers, including low-grade gliomas, certain leukemias, and cholangiocarcinomas. 2-HG inhibits alpha-ketoglutarate–dependent dioxygenases such as TET family DNA demethylases and Jumonji-domain histone demethylases, leading to widespread epigenetic changes and a differentiation block that can contribute to tumor development and maintenance. This mechanistic link has driven the development of targeted inhibitors that selectively block mutant IDH1 or IDH2, lowering 2-HG levels and promoting differentiation of malignant cells. Approved drugs for IDH-mutant cancers include selective IDH inhibitors, which have shown clinically meaningful responses in subsets of patients, especially in acute myeloid leukemia and other IDH-mutant tumors. Ongoing research seeks to understand resistance mechanisms, optimize combination approaches, and extend benefits to additional tumor types 2-hydroxyglutarate Glioma acute myeloid leukemia.
• Diagnostic and prognostic implications: Detection of IDH mutations by sequencing in tumors such as gliomas influences prognosis and treatment planning. Noninvasive imaging approaches, including magnetic resonance spectroscopy to measure 2-HG levels, provide complementary diagnostic insights in some settings. The presence or absence of IDH mutations correlates with distinct clinical outcomes and informs therapeutic decisions, including eligibility for mutation-specific inhibitors magnetic resonance spectroscopy.

Controversies and debates in the field (neutral overview)

• Personalization versus cost and access: The rise of targeted IDH inhibitors illustrates the broader debate about personalized medicine. Supporters emphasize improved outcomes and the ability to tailor therapy to molecular features, while critics stress the premium price, the need for robust biomarker testing, and the risk of uneven access across patient populations. Balancing innovation with affordability remains a live policy and practice discussion in oncology care biomarker.
• Resistance and durability of response: As with many targeted therapies, initial responses to mutant IDH inhibitors can be followed by resistance. Tumor evolution through additional mutations or pathway changes can limit durability, leading to exploration of combination strategies (e.g., IDH inhibitors with other targeted agents, immunotherapy, or epigenetic modulators) to extend benefit and delay progression cancer therapy.
• Broad screening versus selective testing: With IDH mutations being clinically actionable in certain cancers, a debate arises over how broadly to test tumors for these mutations, especially in cancers where the mutation is less common. Proponents argue that even rare actionable targets can justify testing in certain clinical contexts, while others emphasize cost containment and the need for evidence of improved outcomes to justify routine screening genomic testing.

See also

• Tricarboxylic acid cycle
• NADPH
• NADP+
• alpha-ketoglutarate
• 2-hydroxyglutarate
• IDH1
• IDH2
• IDH3
• Glioma
• acute myeloid leukemia