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]
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]
Scheller T, Orgacka H, Szumlanski CL, Weinshilboum RM (1996). "Mouse liver nicotinamide N-methyltransferase pharmacogenetics: biochemical properties and variation in activity among inbred strains". Pharmacogenetics. 6 (1): 43–53. doi:10.1097/00008571-199602000-00003. PMID8845860.
Smith ML, Burnett D, Bennett P, et al. (1998). "A direct correlation between nicotinamide N-methyltransferase activity and protein levels in human liver cytosol". Biochim. Biophys. Acta. 1442 (2–3): 238–44. doi:10.1016/s0167-4781(98)00177-8. PMID9804963.
Kassem HSh, Sangar V, Cowan R, et al. (2002). "A potential role of heat shock proteins and nicotinamide N-methyl transferase in predicting response to radiation in bladder cancer". Int. J. Cancer. 101 (5): 454–60. doi:10.1002/ijc.10631. PMID12216074. S2CID41683922.