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Target intelligence / Profile preview
D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH)
- Target
- D2HGDH
- Molecular classification
- Enzyme, Oxidoreductase, FAD-binding protein, Mitochondrial protein
01
Overview
D-2-hydroxyglutarate dehydrogenase, mitochondrial (D2HGDH), is an FAD-dependent oxidoreductase enzyme that catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate within the mitochondria. It is critical for preventing the toxic accumulation of D-2-HG, which, when elevated, acts as an "oncometabolite" by competitively inhibiting alpha-ketoglutarate–dependent dioxygenases, thereby contributing to epigenetic dysregulation, metabolic reprogramming, and tumorigenesis, especially in IDH-mutant cancers. Mutations in the D2HGDH gene cause D-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by increased D-2-HG in body fluids. The enzyme is a member of the FAD-binding oxidoreductase/transferase type 4 family and is expressed in mitochondria where it supports essential cellular energy and metabolic processes. Currently, there are no approved drugs that directly target D2HGDH, but its product and interconnected pathways serve as diagnostic and prognostic biomarkers in clinical settings.
- Other names
- D2HGDMGC25181FLJ42195D-2-hydroxyglutarate dehydrogenase
02
Mechanism of action
For theoretical drugs: enzyme inhibition or activation, altering D-2-hydroxyglutarate levels (no currently approved modulators)
03
Biological functions
Catalysis of D-2-hydroxyglutarate to alpha-ketoglutarate (also called 2-oxoglutarate)Maintenance of mitochondrial metabolismRegulation of cellular metabolite levels
04
Disease associations
Cancer (especially glioma and IDH-mutant tumors)Neurometabolic disorders (e.g., D-2-hydroxyglutaric aciduria)Other (roles in metabolic reprogramming and potential links to immunological effects via metabolite accumulation)
05
Safety considerations
Potential risk of metabolic disturbances when modulating enzyme activityUnknown off-target metabolic effects due to central role in mitochondrial metabolism
06
Biomarkers
D-2-hydroxyglutarate (D-2-HG) levels (used in diagnosis/monitoring of 2-hydroxyglutaric acidurias and as an oncometabolite biomarker in IDH-mutated cancers)
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