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.
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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.
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Xu J, Capezzone M, Xu X, Hershman JM (2005). "Activation of nicotinamide N-methyltransferase gene promoter by hepatocyte nuclear factor-1beta in human papillary thyroid cancer cells". Mol. Endocrinol. 19 (2): 527–39.
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