Isocitrate Dehydrogenase (IDH) is an enzyme central to cellular metabolism, playing a significant role within the Krebs cycle (tricarboxylic acid or TCA cycle). Normally, IDH catalyzes the conversion of isocitrate into alpha-ketoglutarate (\(\alpha\)-KG), a reaction that also generates the reducing agent NADPH. Specific genetic changes in the \(IDH1\) or \(IDH2\) genes result in a “gain-of-function” mutation, fundamentally altering the enzyme’s catalytic behavior. This alteration gives the enzyme a new biochemical capability that directly contributes to cancer development.
The Creation of the Oncometabolite
The mutated IDH enzyme acquires a neomorphic activity, gaining a function the normal, or wild-type, enzyme does not possess. Instead of converting isocitrate, the mutant enzyme uses its normal product, alpha-ketoglutarate (\(\alpha\)-KG), as a substrate. This reaction pathway results in the production of an abnormal metabolite: D-2-hydroxyglutarate (2-HG).
The mutant IDH enzyme reductively converts \(\alpha\)-KG into 2-HG, consuming the cell’s store of NADPH. The resulting 2-HG is produced in high concentrations, often accumulating to levels more than 100 times higher than in normal cells. This molecule is classified as an “oncometabolite,” promoting the formation and growth of tumors through its accumulation. The production of this abnormal molecule is the central biochemical event driving the pathology of IDH-mutant cancers.
Driving Tumor Growth
The oncogenic effect of 2-HG stems from its close structural resemblance to the normal intermediate, \(\alpha\)-KG. Due to this similarity, accumulated 2-HG acts as a competitive inhibitor, binding to and disabling enzymes that depend on \(\alpha\)-KG for function. The most significant targets of this inhibition are the Ten-Eleven Translocation (TET) DNA demethylases and the Jumonji domain-containing histone demethylases (JmjC-KDMs).
These \(\alpha\)-KG-dependent demethylases remove methyl groups from DNA and histone proteins, a process integral to regulating gene expression. By blocking these enzymes, 2-HG prevents the removal of these chemical tags, leading to widespread DNA methylation (hypermethylation). This epigenetic blockade silences the expression of many genes, including tumor suppressors or those necessary for cell differentiation. The cell becomes trapped in an immature, rapidly dividing state, establishing and progressing the tumor.
Associated Cancers and Diagnostic Screening
IDH mutations are a defining molecular feature in several types of human cancer, with prevalence varying by tumor type. The mutation is most common in lower-grade gliomas, such as oligodendrogliomas and diffuse astrocytomas, found in 70% to over 80% of cases. It is also found in approximately 10 to 20% of Acute Myeloid Leukemia (AML) cases and a similar percentage of intrahepatic cholangiocarcinomas.
Detecting the IDH mutation is important in diagnosis because it influences both prognosis and treatment decisions. For gliomas, the presence of an IDH mutation often indicates a less aggressive disease course and a better prognosis compared to tumors without the mutation. Screening is typically performed using advanced DNA sequencing techniques, such as Next-Generation Sequencing, to identify specific hotspot mutations (R132 in \(IDH1\) or R140 and R172 in \(IDH2\)).
Another diagnostic method involves the direct detection of the oncometabolite, as elevated 2-HG is a molecular signature of the mutation. This can be achieved by measuring 2-HG levels in the blood or urine, or non-invasively in the brain using Magnetic Resonance Spectroscopy (MRS) scans. Immunohistochemistry (IHC), which uses antibodies to detect the mutant IDH1 protein, is a rapid method for initial screening in tissue samples.
Mutation-Specific Treatment Options
The discovery of the mutant enzyme’s unique activity led to the development of IDH inhibitors. These drugs are designed to selectively block the neomorphic function of the mutated enzyme. Examples include Ivosidenib, which targets the mutant IDH1 enzyme, and Enasidenib, which targets the mutant IDH2 enzyme.
These inhibitors bind to an allosteric site on the mutant enzyme, preventing the conversion of \(\alpha\)-KG into the oncogenic 2-HG. Blocking this production causes a rapid and substantial decrease in cellular 2-HG levels. The reduction in 2-HG alleviates the competitive inhibition on the \(\alpha\)-KG-dependent enzymes, allowing the TET demethylases and JmjC-KDMs to regain their normal function. This reversal of the epigenetic block restores normal gene expression and promotes the differentiation of cancerous cells, which can lead to a therapeutic response.