IDLH

Overview

IDH2 (Isocitrate Dehydrogenase 2) is an enzyme that is encoded by the IDH2 gene in humans. It is a part of the isocitrate dehydrogenase family of enzymes, which play a critical role in the citric acid cycle, also known as the Krebs cycle. This enzyme is located in the mitochondria and is involved in the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate and CO2, while reducing NADP+ to NADPH.

Function

IDH2 is crucial for cellular metabolism and energy production. It helps in maintaining the balance of NADPH in the mitochondria, which is essential for reductive biosynthesis and protection against oxidative stress. The enzyme's activity is vital for the proper functioning of the citric acid cycle, which is a central metabolic pathway that provides energy, reducing power, and precursors for biosynthesis.

Clinical Significance

Mutations in the IDH2 gene have been implicated in various types of cancer, including acute myeloid leukemia (AML), gliomas, and chondrosarcomas. These mutations often result in a neomorphic enzyme activity that converts alpha-ketoglutarate to 2-hydroxyglutarate (2-HG), an oncometabolite that can contribute to tumorigenesis by altering cellular epigenetics and metabolism.

IDH2 Mutations in Cancer

Mutations in IDH2 are typically heterozygous and occur at specific arginine residues, most commonly R140 and R172. These mutations lead to the production of 2-HG, which competitively inhibits alpha-ketoglutarate-dependent dioxygenases, affecting histone and DNA methylation and thus altering gene expression.

Therapeutic Target

Due to its role in cancer, IDH2 has become a target for therapeutic intervention. Inhibitors of mutant IDH2, such as enasidenib, have been developed and are used in the treatment of certain cancers, particularly AML. These inhibitors aim to reduce the levels of 2-HG and restore normal cellular function.

Research and Developments

Ongoing research is focused on understanding the broader implications of IDH2 mutations in cancer and other diseases. Studies are also exploring the potential of IDH2 as a biomarker for diagnosis and prognosis, as well as the development of more effective inhibitors.

Also see

• IDH1
• Citric Acid Cycle
• Acute Myeloid Leukemia
• Oncometabolite
• Mitochondria