NNMT

Nicotinamide N-methyltransferase (NNMT) is an enzyme that in humans is encoded by the NNMT gene.^[5] NNMT catalyzes the methylation of nicotinamide and similar compounds using the methyl donor S-adenosyl methionine (SAM-e) to produce S-adenosyl-L-homocysteine (SAH) and 1-methylnicotinamide.^[6]

NNMT
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3ROD, 2IIP
Identifiers
Aliases	NNMT, Nnmt, nicotinamide N-methyltransferase
External IDs	OMIM: 600008; MGI: 1099443; HomoloGene: 4496; GeneCards: NNMT; OMA:NNMT - orthologs
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q23.2 Start 114,257,787 bp[1] End 114,313,285 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A5.3|9 26.45 cM Start 48,503,177 bp[2] End 48,516,453 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tendon of biceps brachii pericardium vena cava Descending thoracic aorta right lobe of liver Achilles tendon ascending aorta popliteal artery tibial arteries gastric mucosa Top expressed in left lobe of liver subcutaneous adipose tissue white adipose tissue intercostal muscle calvaria tunica adventitia of aorta ascending aorta stroma of bone marrow lactiferous gland endothelial cell of lymphatic vessel More reference expression data BioGPS More reference expression data
Gene ontology Molecular function methyltransferase activity transferase activity nicotinamide N-methyltransferase activity pyridine N-methyltransferase activity Cellular component cytoplasm cytosol Biological process methylation animal organ regeneration response to organonitrogen compound NAD biosynthesis via nicotinamide riboside salvage pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4837 18113 Ensembl ENSG00000166741 ENSMUSG00000032271 UniProt P40261 O55239 RefSeq (mRNA) NM_006169 NM_001311062 NM_010924 RefSeq (protein) NP_006160 NP_001358974 NP_001358975 NP_001358976 NP_001297991 NP_035054 Location (UCSC) Chr 11: 114.26 – 114.31 Mb Chr 9: 48.5 – 48.52 Mb PubMed search [3] [4]
Wikidata
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Function

Methylation of nicotinamide by NNMT and SAM-e is the major pathway for degradation of nicotinamide leading to excretion in the urine.^[6]

Clinical significance

NNMT is highly expressed in the human liver.^[6][7] N-methylation is one method by which drug and other xenobiotic compounds are metabolized by the liver.^[6] NNMT expression in adipose tissue is associated with obesity and insulin resistance.^[6][8] Contrary to the negative effects of increased NNMT in adipose tissue, increased NNMT in liver is associated with a better metabolic profile, namely reduced serum triglycerides and free fatty acids.^[8] In adipose tissue, NNMT can lead to methylation depletion, whereas because of the many methylation enzymes in the liver NNMT has a negligible effect on liver methylation.^[6] But in the liver, the 1-methylnicotinamide produced by NNMT degradation of nicotinamide increases sirtuin 1 (SIRT1) by inhibiting degradation of that protein.^[8] Overexpression of SIRT1 in mice has been shown to reduce insulin and fasting glucose, as well as increased metabolism and physical function.^[9]

Abundant availability of nicotinamide leads to depletion of both nicotinamide adenine dinucleotide (NAD+) and SAM-e, resulting in liver steatosis and fibrosis, causing the progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH).^[10]

Human embryonic stem cells expression of NNMT is believed to help maintain the cells in a naive state.^[6]

NNMT expression is significantly upregulated in many cancers, including pancreatic cancer where levels of NNMT enzyme correlate with increased risk of death.^[11] The cause of these correlations has not been established, but may be related to the fact that NNMT enzyme is an inhibitor of DNA repair.^[11] NNMT and 1-methylnicotinamide inhibit autophagy in breast cancer, protecting breast cancer cells against oxidative stress.^[12] NNMT has been suggested to be a biomarker of cancer.^[11]