Isocitrate Dehydrogenase

Definition

Isocitrate dehydrogenase is a key enzyme in the citric acid cycle that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, producing NADH in the process. This enzyme plays a crucial role in regulating the rate and flux of the citric acid cycle, which is central to cellular energy production.

5 Must Know Facts For Your Next Test

1. Isocitrate dehydrogenase catalyzes the conversion of isocitrate to α-ketoglutarate, releasing a molecule of carbon dioxide in the process.
2. The reaction catalyzed by isocitrate dehydrogenase is a rate-limiting step in the citric acid cycle, as it controls the flux of metabolites through the cycle.
3. There are three isoforms of isocitrate dehydrogenase in humans: IDH1 (cytosolic), IDH2 (mitochondrial), and IDH3 (mitochondrial).
4. Isocitrate dehydrogenase plays a key role in regulating the balance between oxidative and reductive metabolism, as it is involved in both the citric acid cycle and the production of NADPH.
5. Mutations in the genes encoding isocitrate dehydrogenase have been associated with various types of cancer, highlighting the enzyme's importance in cellular metabolism and signaling.

Review Questions

• Describe the role of isocitrate dehydrogenase in the citric acid cycle.
  • Isocitrate dehydrogenase is a crucial enzyme in the citric acid cycle, as it catalyzes the conversion of isocitrate to α-ketoglutarate. This reaction is a rate-limiting step in the cycle, meaning it controls the overall flux of metabolites through the pathway. By oxidatively decarboxylating isocitrate, isocitrate dehydrogenase produces NADH, which is then used in the electron transport chain to generate ATP, the primary energy currency of the cell. The regulation of isocitrate dehydrogenase activity is therefore essential for maintaining the proper functioning of the citric acid cycle and cellular energy production.
• Explain the significance of the different isoforms of isocitrate dehydrogenase found in human cells.
  • Humans have three isoforms of isocitrate dehydrogenase: IDH1 (cytosolic), IDH2 (mitochondrial), and IDH3 (mitochondrial). The presence of these distinct isoforms suggests that isocitrate dehydrogenase plays diverse roles in cellular metabolism and regulation. IDH1 and IDH2 are involved in the production of NADPH, which is essential for maintaining cellular redox balance and supporting anabolic pathways. In contrast, IDH3 is the primary isoform responsible for the rate-limiting step in the citric acid cycle, directly contributing to energy production. The differential localization and functions of these isoforms highlight the complex and multifaceted role of isocitrate dehydrogenase in cellular metabolism and homeostasis.
• Discuss the connection between mutations in isocitrate dehydrogenase genes and the development of cancer.
  • Mutations in the genes encoding isocitrate dehydrogenase, particularly IDH1 and IDH2, have been strongly associated with the development of various types of cancer, including gliomas, acute myeloid leukemia, and chondrosarcomas. These mutations result in the production of an altered form of the enzyme that catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG). The accumulation of 2-HG disrupts normal cellular metabolism and signaling, leading to the promotion of tumor growth and the inhibition of cellular differentiation. The critical role of isocitrate dehydrogenase in regulating the balance between oxidative and reductive metabolism, as well as its involvement in cellular signaling pathways, highlights the importance of this enzyme in maintaining cellular homeostasis and preventing the development of cancer.

Related terms

Citric Acid Cycle:

Also known as the Krebs cycle, the citric acid cycle is a series of chemical reactions that occur in the mitochondria of cells, where it plays a central role in cellular respiration and energy production.

Decarboxylation:

The removal of a carboxyl group (–COOH) from a molecule, typically resulting in the release of carbon dioxide (CO2).

NADH:

Nicotinamide adenine dinucleotide (NADH) is a coenzyme that is produced during the citric acid cycle and is used in the electron transport chain to generate ATP, the primary energy currency of the cell.