GO:0051990 (R)-2-hydroxyglutarate dehydrogenase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0051990 describes the molecular function that catalyzes the reaction (R)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor, also known as D-2-hydroxyglutarate dehydrogenase activity.
• The enzyme is central to the metabolism of the oncometabolite (R)-2-hydroxyglutarate (R-2HG), which is produced in excess by neomorphic IDH1 and IDH2 mutations in cancer.
• R-2HG acts as a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases, including TET enzymes and histone demethylases, linking this activity to epigenetic dysregulation.
• R-2HG also modulates m6A RNA methylation by targeting FTO, affecting MYC/CEBPA signaling and aerobic glycolysis in leukemia.
• Loss or inhibition of (R)-2-hydroxyglutarate dehydrogenase activity can elevate R-2HG levels, contributing to tumorigenesis, immune evasion, and necroptosis in IDH-mutated AML.
• Research on this activity uses CRISPR knockout, point mutation, knock-in, and overexpression models combined with metabolomics, RNA-seq, and m6A profiling to dissect its roles in cancer and metabolism.
Description
GO:0051990, (R)-2-hydroxyglutarate dehydrogenase activity, is a molecular function that catalyzes the oxidation of (R)-2-hydroxyglutarate (R-2HG) to 2-oxoglutarate (alpha-ketoglutarate) while reducing an electron acceptor. This activity is critical for maintaining cellular levels of R-2HG, a metabolite that has gained prominence as an oncometabolite in cancers harboring mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2. The enzyme provides a direct biochemical link between R-2HG catabolism and the regulation of alpha-ketoglutarate-dependent dioxygenases, which are involved in DNA and histone demethylation. Dysregulation of (R)-2-hydroxyglutarate dehydrogenase activity leads to accumulation of R-2HG, which inhibits multiple alpha-ketoglutarate-dependent enzymes, including TET2 and JmjC-domain histone demethylases, thereby altering the epigenetic landscape. In leukemia, R-2HG has been shown to attenuate aerobic glycolysis by targeting the FTO/m6A/PFKP/LDHB axis, revealing a metabolic vulnerability that can be exploited therapeutically. Furthermore, R-2HG exhibits anti-tumor activity by inhibiting FTO and modulating MYC/CEBPA signaling, underscoring the complex roles of this metabolite in cancer biology. Given its central role in R-2HG metabolism, understanding the regulation and function of (R)-2-hydroxyglutarate dehydrogenase activity is essential for developing targeted therapies against IDH-mutant cancers. Recent studies have also linked R-2HG to dsDNA sensing and tumor immunity, as well as to necroptosis in IDH-mutated AML cells, highlighting the broad impact of this activity on cellular stress responses and immune surveillance. This article provides a comprehensive overview of the gene ontology term, its mechanism, associated genes, disease relevance, and research methodologies.
(R)-2-hydroxyglutarate dehydrogenase activity At A Glance
| GO ID | GO:0051990 |
|---|---|
| GO term | (R)-2-hydroxyglutarate dehydrogenase activity |
| Ontology | molecular_function |
| Synonym | D-2-hydroxyglutarate dehydrogenase activity |
| Definition | Catalysis of the reaction: (R)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor. |
| Major function | Oxidation of (R)-2-hydroxyglutarate to 2-oxoglutarate, reducing an electron acceptor. |
| Related metabolite | (R)-2-hydroxyglutarate (R-2HG), an oncometabolite produced by mutant IDH1/IDH2. |
| Associated diseases | IDH-mutant cancers, including acute myeloid leukemia and gliomas. |
| Research relevance | Target for understanding oncometabolite clearance and epigenetic regulation. |
What Is GO:0051990?
The term GO:0051990, (R)-2-hydroxyglutarate dehydrogenase activity, is defined by the Gene Ontology as the catalysis of the reaction: (R)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor. In simpler terms, it is the enzyme activity that removes a hydrogen pair from (R)-2-hydroxyglutarate, converting it to 2-oxoglutarate (alpha-ketoglutarate) and transferring the electrons to an acceptor molecule. This activity is synonymous with D-2-hydroxyglutarate dehydrogenase activity and is classified under the molecular_function aspect of the Gene Ontology.
Why Is (R)-2-hydroxyglutarate dehydrogenase activity Important in Cell Biology?
The activity defined by GO:0051990 is crucial because it controls the cellular concentration of (R)-2-hydroxyglutarate, a metabolite that acts as a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. These enzymes include TET family DNA demethylases and JmjC-domain histone demethylases, which are key regulators of the epigenome. Consequently, loss of (R)-2-hydroxyglutarate dehydrogenase activity can lead to R-2HG accumulation, epigenetic dysregulation, and oncogenesis. Moreover, R-2HG has been shown to inhibit FTO, an m6A RNA demethylase, thereby affecting mRNA stability and translation of genes involved in glycolysis and differentiation. The activity is also linked to immune responses, as mutant IDH1 inhibition induces dsDNA sensing and tumor immunity, and to cell death pathways such as necroptosis in AML cells. Therefore, studying this activity provides insights into cancer metabolism, epigenetics, and potential therapeutic strategies.
• Regulates levels of the oncometabolite R-2HG, which inhibits alpha-ketoglutarate-dependent dioxygenases.
• Loss of activity contributes to IDH-mutant cancers by promoting epigenetic changes and metabolic reprogramming.
• Modulates m6A RNA methylation via FTO, impacting MYC/CEBPA signaling and glycolysis in leukemia.
• Influences tumor immunity through dsDNA sensing pathways when mutant IDH1 is inhibited.
• Plays a role in necroptosis regulation in IDH-mutated AML cells.
• Provides a potential therapeutic target for cancers with IDH mutations.
• Helps maintain mitochondrial metabolism and hypoxia tolerance, as suggested by studies in Drosophila.
• Essential for understanding the metabolic and epigenetic crosstalk in cancer and normal physiology.
Molecular Mechanism of (R)-2-hydroxyglutarate dehydrogenase activity
Substrate Recognition and Binding
In simple terms: The enzyme grabs (R)-2-hydroxyglutarate and holds it in place to start the reaction.
The enzyme specifically binds (R)-2-hydroxyglutarate (R-2HG) as its substrate, distinguishing it from the S-enantiomer. This stereospecificity is critical for its biological function. The binding site accommodates the hydroxyl group and carboxyl groups of R-2HG, positioning them for catalysis. Although the exact structural details of the human enzyme are not fully resolved, studies on related dehydrogenases suggest a conserved fold. The reaction requires an electron acceptor, which is reduced as R-2HG is oxidized to 2-oxoglutarate.
Catalytic Mechanism and Electron Transfer
In simple terms: The enzyme removes hydrogen from the substrate and passes electrons to an acceptor molecule.
The catalytic mechanism involves the oxidation of (R)-2-hydroxyglutarate to 2-oxoglutarate, with concomitant reduction of an electron acceptor. This is a typical dehydrogenase reaction where a hydride ion is transferred from the substrate to the acceptor, likely NAD(P)+ or a similar cofactor. The reaction is reversible under certain conditions, but in vivo it primarily drives R-2HG catabolism. The activity is essential for preventing R-2HG accumulation, which would otherwise inhibit alpha-ketoglutarate-dependent enzymes.
Cofactors and Energetics
In simple terms: The enzyme needs a helper molecule to accept electrons and keep the reaction going.
The reaction catalyzed by (R)-2-hydroxyglutarate dehydrogenase requires an electron acceptor, which is reduced to a reduced acceptor. While the specific physiological acceptor for the human enzyme is not definitively established, many dehydrogenases use NAD+ or NADP+. The reaction is energetically favorable under cellular conditions, contributing to the maintenance of low R-2HG levels. The reduced acceptor can be re-oxidized by the electron transport chain, linking this activity to mitochondrial metabolism.
Regulation of Enzyme Activity
In simple terms: The enzyme's activity can be turned up or down by cellular signals.
The activity of (R)-2-hydroxyglutarate dehydrogenase is regulated at multiple levels. Expression levels of the encoding gene can be modulated by transcription factors and epigenetic mechanisms. Additionally, the enzyme's activity may be influenced by the availability of substrates and cofactors, as well as by post-translational modifications. In cancer, mutations in IDH1/IDH2 lead to overproduction of R-2HG, which can overwhelm the dehydrogenase capacity, resulting in its accumulation. Furthermore, R-2HG itself can inhibit alpha-ketoglutarate-dependent enzymes, creating a feedback loop that affects cellular metabolism.
Key Genes Involved in GO:0051990 (R)-2-hydroxyglutarate dehydrogenase activity
The following genes and proteins are directly or indirectly associated with (R)-2-hydroxyglutarate dehydrogenase activity and its biological context.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IDH1 | Mutations produce R-2HG; wild-type catalyzes isocitrate to alpha-ketoglutarate | Oncogenic driver in AML and gliomas; target for inhibitors |
| IDH2 | Mitochondrial isoform; mutations produce R-2HG | Oncogenic driver in AML; target for inhibitors |
| D2HGDH | Encodes D-2-hydroxyglutarate dehydrogenase, the enzyme for GO:0051990 | Loss causes D-2-hydroxyglutaric aciduria; potential tumor suppressor |
| FTO | m6A RNA demethylase; inhibited by R-2HG | Mediates R-2HG effects on glycolysis and differentiation |
| TET2 | DNA demethylase; inhibited by R-2HG | Epigenetic regulation; mutated in leukemia |
| KDM4A | Histone demethylase; inhibited by R-2HG | Epigenetic regulation |
| PFKP | Glycolytic enzyme; regulated via FTO/m6A axis | R-2HG attenuates aerobic glycolysis |
| LDHB | Lactate dehydrogenase B; regulated via FTO/m6A axis | R-2HG attenuates aerobic glycolysis |
| MYC | Transcription factor; modulated by R-2HG via FTO | R-2HG anti-tumor activity |
| CEBPA | Transcription factor; modulated by R-2HG via FTO | R-2HG anti-tumor activity |
| RIPK3 | Kinase involved in necroptosis; R-2HG-induced necroptosis requires RIPK3 | IDH-mutated AML cell death |
| CGAS | dsDNA sensor; activated upon mutant IDH1 inhibition | Tumor immunity |
| STING1 | Adaptor in dsDNA sensing pathway | Tumor immunity |
| L2HGDH | L-2-hydroxyglutarate dehydrogenase; related enzyme | Mitochondrial metabolism and hypoxia tolerance |
| SDHA | Succinate dehydrogenase; related metabolic enzyme | Mitochondrial metabolism |
| FH | Fumarate hydratase; related metabolic enzyme | Mitochondrial metabolism |
| MDH2 | Malate dehydrogenase; related metabolic enzyme | Mitochondrial metabolism |
| GOT2 | Glutamate oxaloacetate transaminase; related to alpha-ketoglutarate metabolism | Mitochondrial metabolism |
How Is (R)-2-hydroxyglutarate dehydrogenase activity Regulated?
The activity of (R)-2-hydroxyglutarate dehydrogenase is regulated by the availability of its substrate (R)-2-hydroxyglutarate, which is produced by mutant IDH1/IDH2 enzymes. In cancer cells, neomorphic IDH mutations lead to excessive R-2HG production, potentially overwhelming the dehydrogenase capacity and causing R-2HG accumulation. Additionally, the expression of the D2HGDH gene may be subject to transcriptional and epigenetic regulation, although specific mechanisms are not fully elucidated. The activity is also influenced by the cellular redox state, as it requires an electron acceptor. Furthermore, R-2HG can inhibit alpha-ketoglutarate-dependent dioxygenases, which may indirectly affect cellular metabolism and gene expression, creating feedback loops that impact dehydrogenase activity.
(R)-2-hydroxyglutarate dehydrogenase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IDH1 | Acute myeloid leukemia, glioma | Knock-in of IDH1 R132H mutation in cell lines; xenograft models |
| IDH2 | Acute myeloid leukemia | Knock-in of IDH2 R140Q or R172K mutations |
| D2HGDH | D-2-hydroxyglutaric aciduria | Knockout of D2HGDH in cell lines; metabolomics |
| FTO | Leukemia, metabolic regulation | Overexpression or knockout of FTO; m6A profiling |
| RIPK3 | Necroptosis in AML | Knockout of RIPK3 in IDH-mutated AML cells; cell death assays |
IDH-Mutant Cancers
Mutations in IDH1 and IDH2 are common in acute myeloid leukemia, gliomas, and other cancers. These mutations confer a neomorphic activity that converts alpha-ketoglutarate to (R)-2-hydroxyglutarate, which accumulates to high levels. The excess R-2HG inhibits alpha-ketoglutarate-dependent dioxygenases, including TET2 and histone demethylases, leading to DNA and histone hypermethylation and altered gene expression. This epigenetic dysregulation contributes to oncogenesis. Loss of (R)-2-hydroxyglutarate dehydrogenase activity would exacerbate R-2HG accumulation, but the primary driver is the mutant IDH enzymes. Therapeutic strategies include mutant IDH inhibitors, which reduce R-2HG levels and induce differentiation or immune responses.
D-2-Hydroxyglutaric Aciduria
Deficiency in D-2-hydroxyglutarate dehydrogenase, the enzyme encoded by D2HGDH, causes D-2-hydroxyglutaric aciduria, a rare neurometabolic disorder characterized by elevated R-2HG levels in body fluids. Although not directly cited in the provided references, this condition underscores the importance of the dehydrogenase in clearing R-2HG. The accumulation of R-2HG in the brain can lead to neurological symptoms. Research on this enzyme activity is thus relevant to understanding both rare metabolic diseases and cancer.
Leukemia and Metabolic Reprogramming
In IDH-mutated leukemia, R-2HG attenuates aerobic glycolysis by targeting the FTO/m6A/PFKP/LDHB axis, reducing glycolytic flux and affecting cell proliferation. Additionally, R-2HG exhibits anti-tumor activity by inhibiting FTO and modulating MYC/CEBPA signaling, which can suppress leukemogenesis. However, R-2HG can also induce necroptosis in IDH-mutated AML cells through RIPK3-dependent pathways, suggesting a complex role in cell death. These findings highlight the therapeutic potential of modulating R-2HG levels via dehydrogenase activity.
Tumor Immunity
Inhibition of mutant IDH1 induces dsDNA sensing and activates tumor immunity, as shown by increased cGAS-STING signaling. This suggests that reducing R-2HG levels, potentially by enhancing dehydrogenase activity, could boost anti-tumor immune responses. The interplay between R-2HG metabolism and immune surveillance is an active area of research.
From (R)-2-hydroxyglutarate dehydrogenase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of D2HGDH increase R-2HG levels? | D2HGDH knockout cell lines (e.g., HEK293, U87) with metabolomics |
| Does mutant IDH1 produce R-2HG that affects gene expression? | IDH1 R132H knock-in in leukemia cell lines; RNA-seq and m6A-seq |
| Can overexpression of D2HGDH reduce R-2HG and reverse epigenetic changes? | D2HGDH overexpression in IDH-mutant cells; histone methylation assays |
| What is the role of R-2HG in necroptosis? | RIPK3 knockout in IDH-mutated AML cells; necroptosis induction |
| Does R-2HG affect glycolysis via FTO? | FTO knockout or overexpression; glycolysis assays and m6A profiling |
| Can mutant IDH1 inhibition activate immune response? | IDH1 mutant cells treated with inhibitors; dsDNA sensing assays |
How to Study the (R)-2-hydroxyglutarate dehydrogenase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Levels of R-2HG, 2-oxoglutarate, and other metabolites | Assessing dehydrogenase activity and oncometabolite accumulation |
| m6A-seq/MeRIP | m6A RNA methylation sites and abundance | Studying FTO inhibition by R-2HG |
| RNA-seq | Transcriptome changes | Identifying gene expression changes due to R-2HG |
| ChIP-seq | Histone modifications and transcription factor binding | Epigenetic effects of R-2HG |
| Bisulfite sequencing | DNA methylation patterns | TET inhibition by R-2HG |
| CRISPR knockout | Gene function loss | Studying D2HGDH, FTO, RIPK3 roles |
| CRISPR knock-in | Introduction of specific mutations | Modeling IDH1/2 mutations |
| Immunoblotting | Protein expression and modification | Validating pathway changes |
Metabolomics and R-2HG Quantification
Liquid chromatography-mass spectrometry (LC-MS) is used to measure intracellular and extracellular levels of (R)-2-hydroxyglutarate and related metabolites. This method is essential for assessing the impact of (R)-2-hydroxyglutarate dehydrogenase activity on R-2HG accumulation. Studies have used metabolomics to show that mutant IDH1/2 produce high levels of R-2HG.
Epigenetic Profiling
Because R-2HG inhibits alpha-ketoglutarate-dependent dioxygenases, DNA methylation (e.g., 5hmC) and histone methylation (e.g., H3K9me3, H3K27me3) can be assessed by bisulfite sequencing, ChIP-seq, or immunoblotting. These methods reveal the epigenetic consequences of altered dehydrogenase activity.
RNA Methylation (m6A) Analysis
R-2HG inhibits FTO, affecting m6A RNA methylation. m6A-seq and MeRIP-qPCR can map m6A sites and quantify changes. This approach has been used to show that R-2HG modulates the FTO/m6A/PFKP/LDHB axis in leukemia and affects MYC/CEBPA signaling.
CRISPR-Based Genetic Models
CRISPR/Cas9 knockout, knock-in, and point mutation models are powerful tools to study the function of genes involved in (R)-2-hydroxyglutarate dehydrogenase activity. For example, knocking out D2HGDH or introducing IDH1 mutations allows researchers to dissect the metabolic and epigenetic effects. These models can be combined with the methods above to elucidate mechanisms.
How CRISPR Can Be Used to Study GO:0051990 (R)-2-hydroxyglutarate dehydrogenase activity
Knockout
CRISPR knockout of D2HGDH, the gene encoding (R)-2-hydroxyglutarate dehydrogenase, can be used to create cell models with loss of enzyme activity. These models are valuable for studying the consequences of R-2HG accumulation, including epigenetic changes and metabolic reprogramming. Knockout of other genes in the pathway, such as FTO or RIPK3, helps dissect downstream effects.
Point Mutation
Point mutations in IDH1 (e.g., R132H) and IDH2 (e.g., R140Q) are common in cancer and can be introduced using CRISPR knock-in to create isogenic cell lines. These models produce high levels of R-2HG and are used to study the impact on cellular metabolism, epigenetics, and immune responses.
Knock-in
Knock-in of tagged versions of D2HGDH or other enzymes allows for localization and interaction studies. Additionally, knock-in of mutant IDH alleles enables the study of neomorphic activity in a controlled genetic background. These models are essential for understanding the molecular mechanisms of (R)-2-hydroxyglutarate dehydrogenase activity in disease.
Overexpression
Overexpression of D2HGDH can be achieved by CRISPR activation or lentiviral delivery. This approach is used to test whether increasing dehydrogenase activity reduces R-2HG levels and reverses R-2HG-induced phenotypes, such as altered glycolysis or gene expression.
How EDITGENE Supports (R)-2-hydroxyglutarate dehydrogenase activity Research
Researchers studying (R)-2-hydroxyglutarate dehydrogenase activity-related genes often need to determine whether a candidate gene is causally involved in R-2HG metabolism, epigenetic regulation, or cancer phenotypes. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations and knock-in models.
Contact EDITGENE today to design your custom CRISPR model for (R)-2-hydroxyglutarate dehydrogenase activity research.
Frequently Asked Questions About (R)-2-hydroxyglutarate dehydrogenase activity
What is (R)-2-hydroxyglutarate dehydrogenase activity?
It is the enzyme activity defined by GO:0051990 that catalyzes the conversion of (R)-2-hydroxyglutarate to 2-oxoglutarate, reducing an electron acceptor.
What genes are involved in (R)-2-hydroxyglutarate dehydrogenase activity?
The primary gene is D2HGDH, which encodes the enzyme. Related genes include IDH1 and IDH2, which produce R-2HG, and FTO, TET2, and others affected by R-2HG.
How is (R)-2-hydroxyglutarate dehydrogenase activity related to cancer?
Loss of this activity leads to R-2HG accumulation, which inhibits alpha-ketoglutarate-dependent dioxygenases and promotes oncogenesis, especially in IDH-mutant cancers.
What is the role of R-2HG in leukemia?
R-2HG attenuates aerobic glycolysis via the FTO/m6A/PFKP/LDHB axis and exhibits anti-tumor activity by targeting MYC/CEBPA signaling.
Can CRISPR be used to study (R)-2-hydroxyglutarate dehydrogenase activity?
Yes, CRISPR knockout, knock-in, and point mutation models are widely used to study D2HGDH, IDH1/2, and related genes.
What diseases are associated with (R)-2-hydroxyglutarate dehydrogenase deficiency?
D-2-hydroxyglutaric aciduria is a rare neurometabolic disorder caused by D2HGDH deficiency. IDH mutations are associated with AML and gliomas.
How does R-2HG affect the immune system?
Inhibition of mutant IDH1 induces dsDNA sensing and activates tumor immunity through cGAS-STING signaling.
What methods are used to measure (R)-2-hydroxyglutarate dehydrogenase activity?
LC-MS metabolomics, m6A-seq, RNA-seq, and epigenetic profiling are commonly used to assess activity and its downstream effects.
Is (R)-2-hydroxyglutarate dehydrogenase a tumor suppressor?
D2HGDH loss can contribute to R-2HG accumulation, but its role as a tumor suppressor is context-dependent and not fully established.
What are the therapeutic implications of targeting (R)-2-hydroxyglutarate dehydrogenase activity?
Modulating this activity could reduce R-2HG levels and reverse its oncogenic effects, offering a potential strategy for IDH-mutant cancers.
Conclusion
GO:0051990, (R)-2-hydroxyglutarate dehydrogenase activity, is a critical molecular function that regulates the cellular levels of the oncometabolite R-2HG. Through its role in converting R-2HG to 2-oxoglutarate, it influences epigenetic states, metabolic pathways, and immune responses. Dysregulation of this activity, often through mutations in IDH1/IDH2 or loss of D2HGDH, contributes to cancer and rare metabolic disorders. Understanding the mechanisms and regulation of this enzyme provides opportunities for therapeutic intervention, particularly in IDH-mutant malignancies. Continued research using advanced CRISPR models and multi-omics approaches will further elucidate its biological significance and clinical potential.
References
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- 2. Xu W et al.. 2011. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.. Cancer Cell 19(1):17-30 PMID: 21251613
- 3. Dang L et al.. 2009. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.. Nature 462(7274):739-44 PMID: 19935646
- 4. Wu MJ et al.. 2024. Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.. Science 385(6705):eadl6173 PMID: 38991060
- 5. Su R et al.. 2018. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m(6)A/MYC/CEBPA Signaling.. Cell 172(1-2):90-105.e23 PMID: 29249359
- 6. Zhu S et al.. 2024. RIPK3 deficiency blocks R-2-hydroxyglutarate-induced necroptosis in IDH-mutated AML cells.. Sci Adv 10(16):eadi1782 PMID: 38630819
- 7. Mahmoudzadeh NH et al.. 2024. Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster.. Mol Metab 89:102013 PMID: 39182840
- 8. Ward PS et al.. 2010. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.. Cancer Cell 17(3):225-34 PMID: 20171147
