IDH1 (Isocitrate Dehydrogenase 1) is a cytosolic enzyme that catalyzes the NADP+-dependent conversion of isocitrate to α-ketoglutarate (α-KG), producing NADPH as a byproduct. This enzyme plays critical roles in cellular metabolism, antioxidant defense, and epigenetic regulation. In the brain, IDH1 deficiency has been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions 1. [1]
IDH1 is a homodimeric enzyme localized to the cytosol and peroxisomes. It serves as the primary source of cytosolic NADPH, which is essential for maintaining the reduced glutathione pool and protecting cells from oxidative stress. The enzyme's function intersects with multiple neurodegenerative disease pathways, making it a subject of significant research interest. [2]
| Property | Value | [3]
|----------|-------| [4]
| Gene | IDH1 |
| UniProt ID | O75874 |
| Molecular Weight | ~47 kDa (per subunit) |
| Structure | Homodimer |
| Localization | Cytosol, Peroxisomes |
| EC Number | 1.1.1.42 |
IDH1 forms homodimers with each subunit consisting of three distinct domains 2:
The active site undergoes conformational changes during catalysis, with key residues including Arg132, His179, and Asp279. Wild-type IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate to α-ketoglutarate, producing NADPH.
IDH1 catalyzes the following reaction:
The reaction favors the forward direction but can run in reverse under certain metabolic conditions. Each turn of the cycle produces one molecule of NADPH.
IDH1 serves multiple essential cellular functions:
IDH1 activity is significantly reduced in Alzheimer's disease brain 3:
In Parkinson's disease, IDH1 impairment contributes to dopaminergic neuron vulnerability 4:
While IDH1 dysfunction is relevant to neurodegeneration, IDH1 mutations are well-characterized in cancer:
Given IDH1's role in NADPH production:
The study of Idh1 Protein Isocitrate Dehydrogenase 1 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
IDH1 deficiency in Alzheimer's disease brain (2022). 2022. ↩︎
Crystal structure of human cytosolic NADP-dependent isocitrate dehydrogenase (2021). 2021. ↩︎
Oxidative stress and IDH1 in Alzheimer's disease (2023). 2023. ↩︎
IDH1 and dopaminergic neuron vulnerability in Parkinson's disease (2022). 2022. ↩︎