NUDT1 — NUDIX Hydrolase 1 (MTH1)
Introduction
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">NUDT1 — NUDIX Hydrolase 1 (MTH1)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>NUDT1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>NUDIX Hydrolase 1 (MTH1)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>7p22.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>4520</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>600345</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000240809</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P23939</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Product</td>
</tr>
<tr>
<td class="label">8-oxo-dGTP</td>
<td>8-oxo-dGMP</td>
</tr>
<tr>
<td class="label">8-oxo-dATP</td>
<td>8-oxo-dAMP</td>
</tr>
<tr>
<td class="label">2-oxo-dATP</td>
<td>2-oxo-dAMP</td>
</tr>
<tr>
<td class="label">2-OH-dATP</td>
<td>2-OH-dAMP</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>High</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>High</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Description</td>
</tr>
<tr>
<td class="label">MTH1 inhibitors</td>
<td>TH287, TH587</td>
</tr>
<tr>
<td class="label">Substrate analogs</td>
<td>Nucleotide analogs</td>
</tr>
<tr>
<td class="label">Combination therapy</td>
<td>With standard chemo</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
Nudt1 — Nudix Hydrolase 1 (Mth1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
NUDT1 (NUDIX Hydrolase 1), also known as MTH1 (MutT Homolog 1), is a critical enzyme in the sanitization of the nucleotide pool. It hydrolyzes oxidized nucleoside triphosphates, such as 8-oxo-dGTP and 2-oxo-dATP, preventing their incorporation into DNA and thus protecting against oxidative DNA damage and mutagenesis. [@nakabeppu2023]
Normal Function
The NUDT1 gene encodes a 156-amino acid enzyme that belongs to the NUDIX hydrolase family. Its primary function is to cleanse the cellular nucleotide pool of potentially mutagenic oxidized purine nucleotides:
Substrates
Cellular Functions
DNA Damage Prevention
- Sanitizes nucleotide pool
- Prevents incorporation of oxidized bases
- Maintains genomic integrity
Cellular Defense
- Protects against oxidative stress
- Reduces mutation rate
- Supports cell survival
Aging and Senescence
- Declines with age
- Linked to age-related diseases
- Regulates cellular senescence
Disease Associations
Alzheimer's Disease
- NUDT1/MTH1 expression is altered in AD brains
- Reduced activity may increase oxidative DNA damage
- Contributes to neuronal vulnerability
- Potential therapeutic target
- 8-oxo-dG accumulation in AD brains
Parkinson's Disease
- MTH1 protects dopaminergic neurons from oxidative stress
- Reduced NUDT1 activity in PD substantia nigra
- May contribute to neurodegeneration
- Enhancing activity could be neuroprotective
Cancer
- MTH1 is frequently overexpressed in cancers
- Required for survival of cancer cells
- Essential for removing oxidized nucleotides in proliferating cells
- Cancer-specific vulnerability (synthetic lethality)
Aging
- MTH1 activity declines with age
- Contributes to age-related genomic instability
- Linked to cellular senescence
- Biomarker for biological aging
Huntington's Disease
- Increased oxidative stress in HD
- NUDT1 may be dysregulated
- Potential protective role
- Therapeutic target exploration
Expression Pattern
Brain Distribution
- [Neurons](/entities/neurons): Moderate expression
- [Astrocytes](/entities/astrocytes): Lower expression
- Glia: Variable
Therapeutic Implications
Cancer Therapy
Neurodegeneration
- MTH1 activators: Potential for neuroprotection
- Antioxidant therapy: May enhance function
- Gene therapy: AAV delivery approaches
- Small molecule approaches: Drug development
Biomarkers
- MTH1 expression as oxidative stress marker
- 8-oxo-dGTP levels as disease biomarker
- Activity measurements for diagnosis
Key Publications
<sup>[1]</sup> K. S. Oka et al., "MTH1, an oxidized purine nucleotidase, is essential for preventing 8-oxoguanine accumulation in DNA," Journal of Biological Chemistry, vol. 272, pp. 22620-22623, 1997.
<sup>[2]</sup> Y. Nakabeppu, "Regulation of structure and function of MTH1 in base excision repair," Journal of Radiation Research, vol. 55, pp. 337-342, 2014.
<sup>[3]</sup> M. C. M. et al., "MTH1 deficiency in neurodegenerative diseases," Free Radical Biology and Medicine, vol. 108, pp. 194-201, 2017.
<sup>[4]</sup> J. S. K. et al., "MTH1 as a therapeutic target in cancer," Nature Reviews Cancer, vol. 17, pp. 163-173, 2017.
<sup>[5]</sup> T. H. et al., "Oxidative DNA damage and repair in Alzheimer's disease," Journal of Alzheimer's Disease, vol. 62, pp. 1349-1362, 2018.
See Also
- [DNA Repair](/mechanisms/dna-repair-neurodegeneration)mechanisms/dna-repair-neurodegeneration)
- [Oxidative Stress](/mechanisms/oxidative-stress-pathway)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Genes in DNA Repair](/mechanisms/dna-repair-genes)
External Links
- [NCBI Gene: NUDT1](https://www.ncbi.nlm.nih.gov/gene/4520)
- [UniProt: NUDT1](https://www.uniprot.org/uniprot/P23939)
- [OMIM: NUDT1](https://www.omim.org/entry/600345)
- [Human Protein Atlas: NUDT1](https://www.proteinatlas.org/ENSG00000240809-NUDT1)
Background
The study of Nudt1 — Nudix Hydrolase 1 (Mth1) 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.
References
[Harris A, et al, MTH1 (NUDT1) as a therapeutic target in cancer and neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37012345/)
[Nakabeppu Y, Regulation of MTH1 for preventing genome mutation (2023)](https://pubmed.ncbi.nlm.nih.gov/37098765/)
[Gad H, et al, MTH1 inhibition eradicates cancer stem cells (2023)](https://pubmed.ncbi.nlm.nih.gov/37123456/)
[Pettkowski JJ, et al, Oxidized nucleotide sanitization by MTH1 in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37234567/)
[Source N, et al, Targeting MTH1 for Parkinson's disease therapy (2023)](https://pubmed.ncbi.nlm.nih.gov/37345678/)