2-hydroxyglutarate (2HG) is a naturally occurring metabolite found within the body. While present in healthy individuals, 2HG has attracted scientific interest due to its association with certain health conditions, particularly various cancers. Abnormally high levels of this compound can signal underlying cellular changes, prompting investigations into its origins and biological impact.
Understanding 2-Hydroxyglutarate’s Origins
2-hydroxyglutarate exists in two forms: L-2HG and D-2HG. L-2HG is normally produced in small amounts during cellular metabolism, through enzymes like malate dehydrogenase (MDH) and lactate dehydrogenase (LDH) under conditions like low oxygen or acidic pH. D-2HG is typically cleared by the enzyme D2HGDH in the mitochondria.
The primary reason for elevated D-2HG levels stems from specific genetic alterations, most notably mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. These IDH mutations, such as IDH1 R132 or IDH2 R172, give the enzymes a new, abnormal function. This allows them to convert alpha-ketoglutarate (α-KG), a normal metabolic intermediate, into D-2HG. This abnormal conversion leads to a significant accumulation of D-2HG, often 10 to 100 times higher than normal levels. Such high concentrations cause D-2HG to act as an “oncometabolite,” a metabolite that actively contributes to cancer development and progression.
The Role of Elevated 2-Hydroxyglutarate in Disease
Abnormally high levels of D-2HG exert their harmful effects by interfering with normal cellular processes, particularly those involving enzymes that depend on α-KG. D-2HG is structurally similar to α-KG, allowing it to competitively inhibit these α-KG-dependent enzymes. This inhibition disrupts various cellular functions, including DNA and histone demethylation, which are important for regulating gene expression.
Specifically, D-2HG inhibits the Ten-Eleven Translocation (TET) family of DNA demethylases and the Jumonji-C class of histone demethylases. This inhibition leads to a state of hypermethylation of DNA and histones, which can alter gene expression patterns. Such epigenetic changes can silence tumor suppressor genes and activate genes that promote cell growth, contributing to tumor formation and progression. The accumulation of D-2HG also promotes cancer by stabilizing malignant cells in an undifferentiated, stem-cell-like state, thereby supporting uncontrolled proliferation.
Elevated 2HG is strongly linked to several types of cancers, primarily those with IDH mutations. These include gliomas, which are brain tumors, particularly low-grade gliomas and secondary glioblastomas, where IDH mutations are found in 50% to 80% of cases. In acute myeloid leukemia (AML), an aggressive blood cancer, IDH1 or IDH2 mutations are present in about 10% to 20% of patients. Intrahepatic cholangiocarcinoma (iCCA), a type of bile duct cancer, also frequently harbors IDH1/2 mutations in about 15% of cases.
In these cancers, the overproduction of D-2HG directly contributes to disease development by altering the cell’s epigenetic landscape. For instance, in IDH-mutated gliomas and AML, the epigenetic dysregulation caused by D-2HG leads to a DNA hypermethylation phenotype. This hypermethylation can result in increased methylation of tumor DNA, which is clinically associated with a glioma-associated CpG island hypermethylated phenotype (GCIMP) in brain tumors. D-2HG’s interference with histone and DNA methylation suppresses the normal processes of cellular differentiation.
2-Hydroxyglutarate as a Biomarker and Therapeutic Target
Elevated 2HG, particularly D-2HG, serves as a diagnostic biomarker for specific cancers, especially those characterized by IDH mutations. This allows for non-invasive detection, monitoring of disease progression, and assessment of treatment response. Various methods are employed to detect 2HG, including magnetic resonance spectroscopy (MRS), which can non-invasively measure D-2HG levels in tumors in vivo. This technique utilizes the distinctive magnetic resonance signals of 2HG to identify IDH-mutated tumors, offering a way to classify brain tumors without needing a tissue biopsy.
Beyond imaging, liquid biopsies, such as blood or urine tests, are also being explored for 2HG detection. Elevated serum D-2HG concentrations have shown promise in diagnosing IDH-mutant acute myeloid leukemia, with studies reporting high sensitivity and specificity. While urinary 2HG levels have not consistently shown elevation in IDH-mutant glioma patients, the ratio of D-2HG to L-2HG in circulating blood has demonstrated potential as a sensitive and specific biomarker for IDH1/2 mutations in cholangiocarcinoma. Mass spectrometry methods, including gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), are also used to precisely quantify 2HG enantiomers in biological samples.
The understanding of 2HG’s role as an oncometabolite has led to the development of targeted therapeutic strategies. IDH inhibitors are a class of drugs specifically designed to block the abnormal production of 2HG by mutated IDH enzymes. Examples include ivosidenib, which targets mutant IDH1, and enasidenib, which targets mutant IDH2. These inhibitors work by selectively binding to the mutated IDH enzymes, thereby reducing the excessive levels of 2HG.
By lowering 2HG levels, these drugs aim to reverse the epigenetic changes and restore normal cellular differentiation, which can lead to a reduction in cancer cell proliferation. Ivosidenib and enasidenib have received approval for treating IDH-mutated acute myeloid leukemia, and other IDH inhibitors like vorasidenib are showing promise in clinical trials for IDH-mutant gliomas. These targeted therapies offer more specific and potentially less toxic treatment options for patients with IDH-mutated cancers.