2-hydroxyglutarate (2-HG) is a metabolite naturally present in the human body at low, harmless levels. However, specific genetic changes can cause 2-HG to accumulate to abnormally high concentrations within cells. This accumulation has led to its identification as an “oncometabolite,” a molecule that directly contributes to the development and progression of certain cancers.
The Production of 2-HG
The production of 2-HG involves enzymes called isocitrate dehydrogenases (IDH1 and IDH2). In healthy cells, these enzymes participate in the Krebs cycle by converting isocitrate into alpha-ketoglutarate (α-KG). When a specific mutation occurs in the gene for IDH1 or IDH2, it alters the enzyme’s structure and gives it a new, abnormal function. Instead of its normal role, the mutated enzyme aggressively converts α-KG into D-2-hydroxyglutarate (D-2-HG).
This new function leads to a massive buildup of D-2-HG, with levels reaching thousands of times higher than normal. While a different form, L-2-HG, is produced at very low levels in healthy cells, it is the D-2-HG from mutant IDH enzymes that is the primary oncometabolite.
The Oncogenic Function of 2-HG
Accumulated D-2-HG disrupts cellular functions by interfering with a wide range of enzymes. Because D-2-HG is structurally similar to α-KG, it competitively inhibits enzymes that depend on α-KG to function. This interference has profound consequences for epigenetic regulation, which controls how genes are switched on and off without changing the DNA sequence.
A primary target of D-2-HG are the TET enzymes, which are α-KG-dependent. These enzymes are responsible for DNA demethylation, a process that removes methyl groups from DNA. By blocking TET enzymes, D-2-HG causes widespread DNA hypermethylation, which silences genes that suppress tumors or guide cell development, much like a light switch getting stuck in the “off” position.
This epigenetic disruption directly leads to a block in cellular differentiation. Immature cells, such as hematopoietic progenitor cells in the bone marrow, rely on precise gene expression to mature into specialized forms like red or white blood cells. The hypermethylation caused by D-2-HG silences the genes necessary for this maturation process. As a result, these young cells fail to differentiate and remain in a proliferative, undifferentiated state, a defining characteristic of cancers like acute myeloid leukemia.
Cancers Driven by 2-HG
IDH mutations and the resulting 2-HG accumulation are frequent in a specific subset of tumors, redefining their classification. One of the most common areas is in brain tumors, particularly lower-grade gliomas and the secondary glioblastomas that can develop from them. IDH mutations are a biomarker for these specific brain cancers.
Another cancer type driven by this oncometabolite is acute myeloid leukemia (AML), a cancer of the blood and bone marrow. Approximately 20-30% of AML patients have mutations in the IDH1 or IDH2 gene. The presence of these mutations is linked to specific disease characteristics and can affect patient prognosis.
High levels of 2-HG are also a feature of cholangiocarcinoma, a cancer that forms in the bile ducts. The presence of an IDH mutation and 2-HG production is a molecular feature that connects these otherwise distinct diseases.
Detection and Therapeutic Strategies
The link between IDH mutations and 2-HG has created new diagnostic and therapeutic opportunities. Because tumor cells produce 2-HG in large amounts, it serves as a specific biomarker. Doctors can measure its levels in tumor tissue, blood, or urine to confirm a diagnosis of an IDH-mutant cancer and monitor treatment response.
This understanding led to the development of targeted therapies called IDH inhibitors. These drugs are small molecules that block the activity of the mutated IDH1 or IDH2 enzymes. They do not kill cancer cells directly but work by stopping the production of 2-HG.
By halting 2-HG synthesis, the block on cellular differentiation is released. This allows the cancerous, immature cells to resume their normal maturation process, effectively turning them into healthy, functioning cells. Several IDH inhibitors have received FDA approval for treating IDH-mutant AML and cholangiocarcinoma, representing a significant advance in precision medicine.