NNMT Protein

NNMT Protein (Nicotinamide N-Methyltransferase)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">NNMT</th></tr>
<tr><td><b>Gene</b></td><td>[NNMT](/genes/nnmt)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P40261](https://www.uniprot.org/uniprot/P40261)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>30 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytoplasm</td></tr>
<tr><td><b>Protein Family</b></td><td>Nnmt family, methyltransferase</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

NNMT (Nicotinamide N-Methyltransferase) is a cytosolic enzyme that catalyzes the methylation of nicotinamide and other pyridine derivatives using S-adenosyl-L-methionine (SAM) as a methyl donor. The [NNMT](/genes/nnmt) gene is located on chromosome 11q23.2 and is expressed in various tissues, with highest expression in liver and brain.

Structure

NNMT is a single polypeptide enzyme with:

• SAM-binding domain: Conserved methyltransferase fold
• Substrate-binding pocket: Specificity for nicotinamide and analogs
• Active site: Catalytic residues for methyl transfer
• No membrane-spanning regions

The enzyme exists as a monomer in solution.

Biological Function

Nicotinamide Metabolism

NNMT plays a key role in nicotinamide homeostasis:

...

NNMT Protein (Nicotinamide N-Methyltransferase)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">NNMT</th></tr>
<tr><td><b>Gene</b></td><td>[NNMT](/genes/nnmt)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P40261](https://www.uniprot.org/uniprot/P40261)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>30 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytoplasm</td></tr>
<tr><td><b>Protein Family</b></td><td>Nnmt family, methyltransferase</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

NNMT (Nicotinamide N-Methyltransferase) is a cytosolic enzyme that catalyzes the methylation of nicotinamide and other pyridine derivatives using S-adenosyl-L-methionine (SAM) as a methyl donor. The [NNMT](/genes/nnmt) gene is located on chromosome 11q23.2 and is expressed in various tissues, with highest expression in liver and brain.

Structure

NNMT is a single polypeptide enzyme with:

• SAM-binding domain: Conserved methyltransferase fold
• Substrate-binding pocket: Specificity for nicotinamide and analogs
• Active site: Catalytic residues for methyl transfer
• No membrane-spanning regions

The enzyme exists as a monomer in solution.

Biological Function

Nicotinamide Metabolism

NNMT plays a key role in nicotinamide homeostasis:

| Reaction | Product | Function |
|----------|---------|----------|
| Nicotinamide methylation | 1-Methylnicotinamide (MNA) | Detoxification |
| NAD+ precursor recycling | Methylnicotinamide | Metabolite excretion |
| SAM consumption | SAH | Methylation regulation |

Metabolic Regulation

NNMT influences cellular metabolism:

• NAD+ metabolism: Modulates nicotinamide availability for NAD+ synthesis
• Methylation capacity: Consumes SAM, affecting global methylation
• Energy expenditure: Methylation reactions consume ATP

Tissue-Specific Roles

• Liver: Primary site of xenobiotic metabolism
• Brain: Neuronal and glial expression
• Adipose tissue: Linked to metabolic syndrome

Role in Neurodegeneration

Alzheimer's Disease

NNMT is upregulated in AD brain and may contribute to:

NAD+ depletion: Diverts nicotinamide from NAD+ synthesis

Methylation imbalance: Alters DNA/protein methylation patterns

Energy deficit: Impaired mitochondrial function

Neuroinflammation: Glial activation markers correlate

Parkinson's Disease

• Dopaminergic [neurons](/entities/neurons): NNMT expression in substantia nigra
• Metabolic stress: NAD+ metabolism crucial for neuron survival
• Therapeutic response: MNA may have neuroprotective properties

Biomarker Potential

NNMT represents a potential biomarker:

• Blood/CSF levels: Altered in neurodegenerative diseases
• Therapeutic target: Modulation may improve neuronal health
• Disease progression: Correlates with severity markers

Therapeutic Implications

Enzyme Inhibition

NNMT inhibitors show promise for:

• Enhancing NAD+ availability
• Improving neuronal survival
• Modulating methylation status

Neuroprotective Effects

1-Methylnicotinamide (MNA) has demonstrated:

• Anti-inflammatory properties
• Antioxidant effects
• Neuroprotection in models

See Also

• [NNMT Gene](/genes/nnmt)

External Links

• [GeneCards: NNMT](https://www.genecards.org/cgi-bin/carddisp.pl?gene=NNMT)

Clinical Significance

NNMT in disease:

• Cancer: Overexpression in multiple tumors
• Metabolic disorders: Obesity and diabetes
• Neurodegeneration: AD and PD as discussed
• Cardiovascular disease: Atherosclerosis

Therapeutic Strategies

NNMT modulation:

• Inhibitors: Small molecule NNMT inhibitors
• NAD+ precursors: Nicotinamide riboside supplementation
• Combination therapy: With other metabolic modulators

Biomarker Development

NNMT as biomarker:

• Blood NNMT activity
• Tissue expression
• Metabolite profiling (MNA)

Enzyme Kinetics

NNMT catalytic properties:

• Km for nicotinamide: ~50 μM
• Km for SAM: ~5 μM
• Optimal pH: 7.5-8.0
• Inhibitors: Flexible active site

Substrate Specificity

NNMT accepts multiple substrates:

• Nicotinamide: Primary substrate
• Pyridine derivatives: Nicotinic acid
• Quinolinic acid: Tryptophan metabolite
• Isonicotinamide: Structural analog

References

[Liu et al., NNMT in neurodegeneration (2018) (2018)](https://doi.org/10.1016/j.tins.2018.02.005)

[Riederer et al., NNMT in AD brain (2019) (2019)](https://doi.org/10.1007/s00401-019-01993-2)

[Sampat et al., NNMT metabolic function (2016) (2016)](https://doi.org/10.1016/j.tips.2016.06.005)