P40261 · NNMT_HUMAN
- ProteinNicotinamide N-methyltransferase
- GeneNNMT
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids264 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Catalyzes the N-methylation of nicotinamide using the universal methyl donor S-adenosyl-L-methionine to form N1-methylnicotinamide and S-adenosyl-L-homocysteine, a predominant nicotinamide/vitamin B3 clearance pathway (PubMed:21823666, PubMed:23455543, PubMed:8182091).
Plays a central role in regulating cellular methylation potential, by consuming S-adenosyl-L-methionine and limiting its availability for other methyltransferases. Actively mediates genome-wide epigenetic and transcriptional changes through hypomethylation of repressive chromatin marks, such as H3K27me3 (PubMed:23455543, PubMed:26571212, PubMed:31043742).
In a developmental context, contributes to low levels of the repressive histone marks that characterize pluripotent embryonic stem cell pre-implantation state (PubMed:26571212).
Acts as a metabolic regulator primarily on white adipose tissue energy expenditure as well as hepatic gluconeogenesis and cholesterol biosynthesis. In white adipocytes, regulates polyamine flux by consuming S-adenosyl-L-methionine which provides for propylamine group in polyamine biosynthesis, whereas by consuming nicotinamide controls NAD+ levels through the salvage pathway (By similarity).
Via its product N1-methylnicotinamide regulates protein acetylation in hepatocytes, by repressing the ubiquitination and increasing the stability of SIRT1 deacetylase (By similarity).
Can also N-methylate other pyridines structurally related to nicotinamide and play a role in xenobiotic detoxification (PubMed:30044909).
Plays a central role in regulating cellular methylation potential, by consuming S-adenosyl-L-methionine and limiting its availability for other methyltransferases. Actively mediates genome-wide epigenetic and transcriptional changes through hypomethylation of repressive chromatin marks, such as H3K27me3 (PubMed:23455543, PubMed:26571212, PubMed:31043742).
In a developmental context, contributes to low levels of the repressive histone marks that characterize pluripotent embryonic stem cell pre-implantation state (PubMed:26571212).
Acts as a metabolic regulator primarily on white adipose tissue energy expenditure as well as hepatic gluconeogenesis and cholesterol biosynthesis. In white adipocytes, regulates polyamine flux by consuming S-adenosyl-L-methionine which provides for propylamine group in polyamine biosynthesis, whereas by consuming nicotinamide controls NAD+ levels through the salvage pathway (By similarity).
Via its product N1-methylnicotinamide regulates protein acetylation in hepatocytes, by repressing the ubiquitination and increasing the stability of SIRT1 deacetylase (By similarity).
Can also N-methylate other pyridines structurally related to nicotinamide and play a role in xenobiotic detoxification (PubMed:30044909).
Miscellaneous
Prominently expressed in the stroma of high-grade serous carcinomas (PubMed:31043742).
In tumorigenesis, regulates the epigenetic reprograming of cancer cells associated with increased cell migration and metastasis (PubMed:23455543, PubMed:31043742).
In tumorigenesis, regulates the epigenetic reprograming of cancer cells associated with increased cell migration and metastasis (PubMed:23455543, PubMed:31043742).
Catalytic activity
- nicotinamide + S-adenosyl-L-methionine = 1-methylnicotinamide + S-adenosyl-L-homocysteineThis reaction proceeds in the forward direction.
Activity regulation
Inactivated by deimination on Arg-132.
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
0.43 mM | nicotinamide | 7.5 | 37 | |||
0.105 mM | nicotinamide | 8.6 | 37 | |||
1.8 μM | S-adenosyl-L-methionine | 7.5 | 37 | |||
5 μM | S-adenosyl-L-methionine | 8.6 | 37 |
Pathway
Cofactor metabolism.
Amino-acid degradation.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 20 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 25 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 63 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Binding site | 69 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 85 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 90 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 142-143 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: DV | ||||||
Binding site | 163 | S-adenosyl-L-methionine (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 197 | nicotinamide (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 213 | nicotinamide (UniProtKB | ChEBI) | ||||
Sequence: S |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytosol | |
Molecular Function | nicotinamide N-methyltransferase activity | |
Molecular Function | pyridine N-methyltransferase activity | |
Biological Process | animal organ regeneration | |
Biological Process | methylation | |
Biological Process | NAD biosynthesis via nicotinamide riboside salvage pathway | |
Biological Process | nicotinamide metabolic process | |
Biological Process | positive regulation of gluconeogenesis | |
Biological Process | positive regulation of protein deacetylation | |
Biological Process | response to organonitrogen compound | |
Biological Process | response to xenobiotic stimulus |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameNicotinamide N-methyltransferase
- EC number
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP40261
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 18 | Has no effect on N-methyltransferase activity. | ||||
Sequence: R → K | ||||||
Mutagenesis | 20 | Loss of N-methyltransferase activity. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 20 | Decreases N-methyltransferase activity. | ||||
Sequence: Y → F | ||||||
Mutagenesis | 132 | Loss of N-methyltransferase activity like its citrullinated counterpart. | ||||
Sequence: R → K | ||||||
Mutagenesis | 181 | Has no effect on N-methyltransferase activity. | ||||
Sequence: R → K | ||||||
Mutagenesis | 197 | Loss of N-methyltransferase activity. | ||||
Sequence: D → A | ||||||
Mutagenesis | 201 | Has no effect on N-methyltransferase activity. | ||||
Sequence: S → A | ||||||
Mutagenesis | 213 | Has no effect on N-methyltransferase activity. | ||||
Sequence: S → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 420 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000159706 | 1-264 | UniProt | Nicotinamide N-methyltransferase | |||
Sequence: MESGFTSKDTYLSHFNPRDYLEKYYKFGSRHSAESQILKHLLKNLFKIFCLDGVKGDLLIDIGSGPTIYQLLSACESFKEIVVTDYSDQNLQELEKWLKKEPEAFDWSPVVTYVCDLEGNRVKGPEKEEKLRQAVKQVLKCDVTQSQPLGAVPLPPADCVLSTLCLDAACPDLPTYCRALRNLGSLLKPGGFLVIMDALKSSYYMIGEQKFSSLPLGREAVEAAVKEAGYTIEWFEVISQSYSSTMANNEGLFSLVARKLSRPL | |||||||
Modified residue (large scale data) | 11 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 18 | UniProt | Citrulline; alternate | ||||
Sequence: R | |||||||
Modified residue | 39 | UniProt | N6-acetyllysine | ||||
Sequence: K | |||||||
Modified residue (large scale data) | 108 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 132 | UniProt | Citrulline; alternate | ||||
Sequence: R | |||||||
Modified residue | 181 | UniProt | Citrulline; alternate | ||||
Sequence: R |
Post-translational modification
Deiminated by PADI1 and PADI2.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Predominantly expressed in the liver. A lower expression is seen in the kidney, lung, skeletal muscle, placenta and heart. Not detected in the brain or pancreas.
Gene expression databases
Organism-specific databases
Structure
Sequence
- Sequence statusComplete
- Length264
- Mass (Da)29,574
- Last updated1995-02-01 v1
- Checksum280B12748F4488AC
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
U08021 EMBL· GenBank· DDBJ | AAA19904.1 EMBL· GenBank· DDBJ | mRNA | ||
U20971 EMBL· GenBank· DDBJ | AAA93158.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
U20970 EMBL· GenBank· DDBJ | AAA93158.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC000234 EMBL· GenBank· DDBJ | AAH00234.1 EMBL· GenBank· DDBJ | mRNA |