What is the Difference Between IDH1 and IDH2

The key difference between IDH1 and IDH2 is that isocitrate dehydrogenase 1 (IDH1) is a cytosol enzyme coded by the IDH1 gene in humans, while isocitrate dehydrogenase 2 (IDH2) is a mitochondrial enzyme coded by the IDH2 gene in humans.

Oxidative stress occurs when a biological system like a cell is unable to readily detoxify reactive intermediates (reactive oxygen species) or repair damages caused by reactive intermediates. Disturbances to the normal redox state of the cell can cause toxic effects through the production of peroxides and free radicals. Peroxides and free radicals may damage all components of a cell, including proteins, lipids, and DNA. IDH1 and IDH2 are two enzymatic proteins involved in mitigating oxidative damages to the biological cell.

CONTENTS

1. Overview and Key Difference
2. What is IDH1  
3. What is IDH2
4. Similarities – IDH1 and IDH2
5. IDH1 vs IDH2 in Tabular Form
6. Summary – IDH1 vs IDH2

What is IDH1?

IDH1 is a cytosol enzyme encoded by the IDH1 gene in humans. The IDH1 gene is present in chromosome 2. In a cell, the IDH1 enzyme functions in the cytoplasm, peroxisome, and endoplasmic reticulum. This enzyme catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate. This reaction allows the reduction of NADP+ to NADPH. Since α-ketoglutarate and NADPH function in cellular detoxification processes due to oxidative stress, IDH1 also indirectly participates in mitigating oxidative damages. In addition to the above functions, IDH1 also catalyzes β-oxidation of unsaturated fatty acids in the peroxisomes of liver cells. Moreover, it participates in the regulation of glucose-induced insulin secretion. Other than that, IDH1 acts as the primary producer of NADPH in most tissues, including the brain.

IDH1 gene mutation leads to abnormal production of 2-hydroxyglutarate that inhibits alpha-ketoglutarate-dependent enzymes such as histone and DNA demethylases. This can cause changes to histone and DNA methylation, which triggers tumorigenesis. Mutation in the IDH1 gene causes metaphyseal chondromatosis with aciduria. This gene mutation is also observed in diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma, and secondary glioblastoma. Apart from the above, IDH1 mutation is also seen in human acute myeloid leukemia. Some drugs, such as Ivosidenib that targets acute myeloid leukemia with an IDH1 mutation, have been approved by FDA

What is IDH2?

IDH2 is a mitochondrial enzyme. IDH2 gene encodes this enzyme. IDH2 gene is present in chromosome 15 in humans. Similar to the IDH1 enzyme, the IDH2 enzyme also catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate. IDH2 is mainly found in mitochondria and plays an important role in intermediary metabolism and energy metabolism. This protein tightly interacts with the pyruvate dehydrogenase complex.

Somatic mutation of the IDH2 gene has also been found to be associated with medical conditions like Ollier disease and Maffucci syndrome. Moreover, a mutation in the IDH2 gene is responsible for several other diseases including 2 hydroxyglutaric aciduria, glioma, acute myeloid leukemia, chondrosarcoma, intrahepatic cholangiocarcinoma, and angioimmunoblastic T cell lymphoma. Enasidenib is a drug approved by FDA that targets acute myeloid leukemia with an IDH2 mutation.

What are the Similarities Between IDH1 and IDH2?

• IDH1 and IDH2 are two enzymes involved in mitigating oxidative damages to the biological cell.
• Both are proteins made up of amino acids.
• These enzymes are NADP+ dependent.
• Both enzymes catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate.
• Mutations of their genes can cause different tumors such as glioma, acute myeloid leukemia, chondrosarcoma, intrahepatic cholangiocarcinoma, and angioimmunoblastic T cell lymphoma.
• Mutations of genes respond well to chemotherapy and radiotherapy.

What is the Difference Between IDH1 and IDH2?

IDH1 is a cytosol enzyme encoded by the IDH1 gene in humans, while IDH2 is a mitochondrial enzyme encoded by the IDH2 gene in humans. Thus, this is the key difference between IDH1 and IDH2. Furthermore, the IDH1 gene is located in chromosome 2, while the IDH2 gene is located in chromosome 15.

The below infographic presents the differences between IDH1 and IDH2 in tabular form for side by side comparison.

Summary – IDH1 vs IDH2

IDH1 and IDH2 are two enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate. They also catalyze the reduction of NADP+ to NADPH. Since α-ketoglutarate and NADPH function in cellular detoxification processes due to oxidative stress, IDH1 and IDH2 also indirectly participate in mitigating oxidative damages. IDH1 is a cytosol enzyme, while IDH2 is a mitochondrial enzyme. So, this is the summary of the difference between IDH1 and IDH2.

Reference:

1. “IDH1.” An Overview | ScienceDirect Topics.
2. “IDH2.” An Overview | ScienceDirect Topics.

Image Courtesy:

1. “Wild-type and mutant IDH1 structures” By John H. Morris et al.  Mol Cell Proteomics 2010;9:1703-1715 (CC BY 4.0) via Commons Wikimedia
2. “Protein IDH2 PDB 1lwd” By Emw – Own work (CC BY-SA 3.0) via Commons Wikimedia