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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNNMT, Nnmt, nicotinamide N-methyltransferase
External IDsOMIM: 600008 MGI: 1099443 HomoloGene: 4496 GeneCards: NNMT
Orthologs
SpeciesHumanMouse
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 MbChr 9: 48.5 – 48.52 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

References

  1. GRCh38: Ensembl release 89: ENSG00000166741 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000032271 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Aksoy S, Brandriff BF, Ward A, Little PF, Weinshilboum RM (Mar 1996). "Human nicotinamide N-methyltransferase gene: molecular cloning, structural characterization and chromosomal localization". Genomics. 29 (3): 555–61. doi:10.1006/geno.1995.9966. PMID 8575745.
  6. Pissios P (2017). "Nicotinamide N-Methyltransferase: More Than a Vitamin B3 Clearance Enzym". Trends in Endocrinology and Metabolism. 28 (5): 340–353. doi:10.1016/j.tem.2017.02.004. PMC 5446048. PMID 28291578.
  7. Hwang ES, Song SB (2017). "Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells". Cellular and Molecular Life Sciences. 74 (18): 3347–3362. doi:10.1007/s00018-017-2527-8. PMID 28417163. S2CID 25896400.
  8. Guarino M, Dufour J (2019). "Nicotinamide and NAFLD: Is There Nothing New Under the Sun?". Metabolites. 9 (9): 180. doi:10.3390/metabo9090180. PMC 6780119. PMID 31510030.
  9. Bordone L, Cohen D, Robinson A, Motta MC, Guarente L (2007). "SIRT1 transgenic mice show phenotypes resembling calorie restriction". Aging Cell. 6 (6): 759–767. doi:10.1111/j.1474-9726.2007.00335.x. PMID 17877786. S2CID 16071943.
  10. Komatsu M, Kanda T, Wakino S, Itoh H (2018). "NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism". Scientific Reports. 8 (1): 8637. Bibcode:2018NatSR...8.8637K. doi:10.1038/s41598-018-26882-8. PMC 5988709. PMID 29872122.
  11. Lu XM, Long H (2018). "Nicotinamide N-methyltransferase as a Potential Marker for Cancer". Neoplasma. 65 (5): 656–663. doi:10.4149/neo_2018_171024N680. PMID 29940773.
  12. Yu H, Zhou X, Wang Y, Zhang J (2018). "Nicotinamide N-methyltransferase inhibits autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells". Cancer Cell International. 20: 191. doi:10.1186/s12935-020-01279-8. PMC 7247246. PMID 32489327.

Further reading


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