Nicotinamide N-Methyltransferase Interacts with Enzymes of the Methionine Cycle and Regulates Methyl Donor Metabolism

Biochemistry
Shangyu HongPavlos Pissios

Abstract

Methyl donor balance is critical for epigenetic regulation in cells and is maintained by the so-called methionine cycle proteins that regenerate S-adenosylmethionine (SAM), the universal methyl donor, from homocysteine formed by the activity of methyltransferases. Nnmt is a liver enzyme that methylates nicotinamide, but its role in regulating methyl donor balance in the liver is unclear. In this study, we assessed the effect of altered Nnmt expression on various aspects of methyl donor metabolism in the liver. We found that Nnmt overexpression decreased SAM levels and the SAM/ S-adenosylhomocysteine (SAH) ratio both in vivo and in vitro. Nnmt knockdown did not change methyl donor balance in mouse primary hepatocytes but increased SAM levels and the SAM/SAH ratio when Gnmt, the dominantly expressed methyltransferase in liver, was simultaneously knocked down. Paradoxically, expression of enzymatically deficient Nnmt increased the SAM/SAH ratio, suggesting that Nnmt can regulate methyl donor balance independent of its methyltransferase activity. Proteomics analysis of Nnmt-interacting proteins in the liver identified Bhmt, Mat1a, and Ahcy, all components of the methionine cycle, and functional experiments showed that mutant Nnmt i...Continue Reading

References

Jun 1, 1975·Metabolism: Clinical and Experimental·S H Mudd, J R Poole
Jan 31, 1990·Clinica Chimica Acta; International Journal of Clinical Chemistry·J RiniR M Weinshilboum
Feb 1, 1983·The Journal of Nutrition·Y A Kang-LeeR S Jope
Apr 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·S C LuJ M Mato
May 1, 1990·The Journal of Nutritional Biochemistry·J D Finkelstein
Jan 9, 2007·The American Journal of Clinical Nutrition·S Harvey MuddConrad Wagner
Mar 12, 2008·Annual Review of Nutrition·José M MatoShelly C Lu
Jun 26, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Marta Varela-ReyJosé M Mato
Mar 5, 2013·Nature Chemical Biology·Olesya A UlanovskayaBenjamin F Cravatt

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Citations

Jul 20, 2019·International Journal of Tryptophan Research : IJTR·Adrian C Williams, Lisa J Hill
Jun 18, 2020·International Journal of Tryptophan Research : IJTR·David B RamsdenAdrian C Williams
May 25, 2021·Drug Discovery Today·Yongzhi GaoMatthijs J van Haren
Jun 3, 2021·International Journal of Molecular Sciences·Renata Novak KujundžićKoraljka Gall Trošelj
Oct 8, 2019·Journal of Medicinal Chemistry·Rocco L PolicarpoMatthew D Shair

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