Isocitrate dehydrogenase

Isocitrate dehydrogenase (IDH) is an enzyme that plays a crucial role in the metabolic process, specifically in the citric acid cycle (also known as the Krebs cycle), which is a key part of cellular respiration. This enzyme catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2 while reducing NAD+ to NADH or NADP+ to NADPH, depending on the specific form of the enzyme.

There are several forms of isocitrate dehydrogenase, which are classified based on their location within the cell and their cofactor specificity. The two main types are:

• NAD+-dependent isocitrate dehydrogenase, which is found in the mitochondria and plays a role in the energy-producing reactions of the Krebs cycle.
• NADP+-dependent isocitrate dehydrogenase, which exists in two forms: one is located in the cytoplasm and the other in the mitochondria, both of which are involved in cellular defense against oxidative stress and in lipid and amino acid synthesis.

The importance of IDH in cellular metabolism and energy production makes it a key enzyme for study in biochemistry and molecular biology. Mutations in the genes encoding IDH have been linked to various forms of cancer, making it a target for cancer research. Specifically, mutations in IDH1 and IDH2 genes have been associated with certain types of gliomas, acute myeloid leukemia (AML), and other malignancies. These mutations often result in a gain of function, where the mutant enzyme produces 2-hydroxyglutarate (2HG) instead of alpha-ketoglutarate. The accumulation of 2HG is thought to contribute to the formation and progression of tumors by interfering with cell differentiation and DNA methylation processes.

Research into IDH mutations and their effects on cancer has led to the development of targeted therapies aimed at inhibiting the mutant forms of the enzyme. These inhibitors are designed to restore normal cellular metabolism and reduce the oncogenic potential of cells with IDH mutations.