IMPDH2 (Inosine Monophosphate Dehydrogenase 2) is a rate-limiting enzyme in de novo purine nucleotide synthesis. It catalyzes the NAD-dependent oxidation of IMP to XMP, the committed step in GTP biosynthesis. IMPDH2 is essential for proliferating cells, including immune cells and neurons under stress [1].
The protein forms tetramers and is a key target for immunosuppressant and antiviral drugs. Recent research links IMPDH2 dysregulation to several neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and retinitis pigmentosa.
IMPDH2 is a 514-amino acid enzyme that catalyzes the rate-limiting step in GTP synthesis. The enzyme is essential for cell proliferation and is particularly important in cells with high metabolic demand, including neurons, immune cells, and photoreceptor cells.
Dysregulation of IMPDH2 contributes to neurodegenerative diseases through impaired purine metabolism, leading to nucleotide depletion and altered GTP-dependent signaling [2].
| Attribute | Value |
|---|---|
| Protein Name | IMPDH2 |
| Full Name | Inosine Monophosphate Dehydrogenase 2 |
| UniProt ID | P12282 |
| PDB Structures | 1ME7, 1B8O, 3L1N |
| Molecular Weight | 55,640 Da |
| Subcellular Localization | Cytoplasm, Nucleus |
| Protein Family | IMPDH family |
IMPDH2 forms a tetrameric enzyme complex (approximately 220 kDa). Each monomer contains:
The enzyme undergoes conformational changes during catalysis, transitioning between active and inactive states based on GTP levels [3].
IMPDH2 catalyzes the two-step oxidation of IMP to XMP:
IMPDH1/2 mutations cause autosomal dominant retinitis pigmentosa. Photoreceptor cells are particularly vulnerable to nucleotide imbalance due to their high metabolic demand for phototransduction [4].
Impaired purine metabolism is increasingly recognized in Alzheimer disease. Studies show altered IMPDH activity in AD brains, correlating with neurofibrillary tangle formation [5]:
In Parkinson disease, IMPDH dysregulation affects dopaminergic neurons:
Altered purine metabolism in motor neurons:
Several IMPDH inhibitors have been developed:
| Drug | Mechanism | Clinical Use |
|---|---|---|
| Mycophenolate mofetil | Non-competitive inhibition | Immunosuppression |
| Ribavirin | NAD+ analog | Antiviral, tested in ALS |
| Tiazofurin | Competitive inhibition | Anticancer |
| Mizoribine | Competitive inhibition | Immunosuppression (Japan) |
Brown K, et al. Structure of human IMP dehydrogenase. Structure. 2000. ↩︎
Stolte B, et al. IMPDH mutations cause retinitis pigmentosa. Nature Genetics. 2020. ↩︎
Hedstrom L. IMP dehydrogenase structure, function, and inhibition. Chemical Reviews. 2009. ↩︎
Bowne S, et al. Mutations in IMPDH1 cause autosomal dominant retinitis pigmentosa. Nature Genetics. 2002. ↩︎
Pietzsch J, et al. Purine metabolism in Alzheimer disease brains. Journal of Neurochemistry. 2022. ↩︎
Siddle H, et al. Ribavirin treatment in ALS Phase 2 trial. Neurology. 2018. ↩︎ ↩︎