| NNMT |
|---|
| Gene | [NNMT](/genes/nnmt) |
| UniProt ID | [P40261](https://www.uniprot.org/uniprot/P40261) |
| Molecular Weight | 30 kDa |
| Subcellular Localization | Cytoplasm |
| Protein Family | Nnmt family, methyltransferase |
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 gene is located on chromosome 11q23.2 and is expressed in various tissues, with highest expression in liver and brain.
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.
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 |
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
- Liver: Primary site of xenobiotic metabolism
- Brain: Neuronal and glial expression
- Adipose tissue: Linked to metabolic syndrome
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
- Dopaminergic neurons: NNMT expression in substantia nigra
- Metabolic stress: NAD+ metabolism crucial for neuron survival
- Therapeutic response: MNA may have neuroprotective properties
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
NNMT inhibitors show promise for:
- Enhancing NAD+ availability
- Improving neuronal survival
- Modulating methylation status
1-Methylnicotinamide (MNA) has demonstrated:
- Anti-inflammatory properties
- Antioxidant effects
- Neuroprotection in models
NNMT in disease:
- Cancer: Overexpression in multiple tumors
- Metabolic disorders: Obesity and diabetes
- Neurodegeneration: AD and PD as discussed
- Cardiovascular disease: Atherosclerosis
NNMT modulation:
- Inhibitors: Small molecule NNMT inhibitors
- NAD+ precursors: Nicotinamide riboside supplementation
- Combination therapy: With other metabolic modulators
NNMT as biomarker:
- Blood NNMT activity
- Tissue expression
- Metabolite profiling (MNA)
NNMT catalytic properties:
- Km for nicotinamide: ~50 μM
- Km for SAM: ~5 μM
- Optimal pH: 7.5-8.0
- Inhibitors: Flexible active site
NNMT accepts multiple substrates:
- Nicotinamide: Primary substrate
- Pyridine derivatives: Nicotinic acid
- Quinolinic acid: Tryptophan metabolite
- Isonicotinamide: Structural analog