Exploring NNMT: from Metabolic Pathways to Therapeutic Targets

Overview

Journal Arch Pharm Res

Specialty Pharmacology

Date 2024 Nov 28

PMID 39604638

Authors

Jeongwoo Park

Eun Jin Shin

Tae Hyun Kim

Ji Hye Yang

Sung Hwan Ki

Keon Wook Kang

Kyu Min Kim

Affiliations

Soon will be listed here.

Abstract

Cellular metabolism-related epigenetic modulation plays a pivotal role in the maintenance of cellular homeostasis. Nicotinamide N-methyltransferase (NNMT) serves as a crucial link between cellular metabolism and epigenetics by catalyzing nicotinamide methylation using the universal methyl donor S-adenosyl-L-methionine. This direct connection bridges the methylation-mediated one-carbon metabolism with nicotinamide adenine dinucleotide levels. Numerous studies have revealed tissue-specific differences in NNMT expression and activity, indicating that its varied physiological and pathological roles depend on its distribution. In this review, we provide an overview of the NNMT involvement in various pathological conditions, including cancer, liver disease, obesity, diabetes, brain disease, pulmonary disease, cardiovascular disease, and kidney disease. By synthesizing this information, our article aims to enhance our understanding of the cellular mechanisms underlying NNMT biology related to diverse diseases and lay the molecular groundwork for developing therapeutic strategies for pharmacological interventions.

Citing Articles

Interactions between NAD+ metabolism and immune cell infiltration in ulcerative colitis: subtype identification and development of novel diagnostic models.

Tian L, Gao H, Yao T, Chen Y, Gao L, Han J Front Immunol. 2025; 16:1479421.

PMID: 39975557 PMC: 11835821. DOI: 10.3389/fimmu.2025.1479421.

References

Akar S, Harmankaya I, Ugras S, Celik C . Nicotinamide N-methyltransferase expression and its association with phospho-Akt, p53 expression, and survival in high-grade endometrial cancer. Turk J Med Sci. 2019; 49(5):1547-1554. PMC: 7018241. DOI: 10.3906/sag-1907-166. View

Aksoy S, Szumlanski C, Weinshilboum R . Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization. J Biol Chem. 1994; 269(20):14835-40. View

Aoyama K, Matsubara K, Kondo M, Murakawa Y, Suno M, Yamashita K . Nicotinamide-N-methyltransferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson's disease. Neurosci Lett. 2001; 298(1):78-80. DOI: 10.1016/s0304-3940(00)01723-7. View

Babault N, Allali-Hassani A, Li F, Fan J, Yue A, Ju K . Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). J Med Chem. 2018; 61(4):1541-1551. PMC: 5823789. DOI: 10.1021/acs.jmedchem.7b01422. View

Bitterman K, Anderson R, Cohen H, Latorre-Esteves M, Sinclair D . Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem. 2002; 277(47):45099-107. DOI: 10.1074/jbc.M205670200. View

Brachs S, Polack J, Brachs M, Jahn-Hofmann K, Elvert R, Pfenninger A . Genetic Nicotinamide -Methyltransferase () Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance. Diabetes. 2018; 68(3):527-542. DOI: 10.2337/db18-0780. View

Bromberg A, Lerer E, Udawela M, Scarr E, Dean B, Belmaker R . Nicotinamide-N-methyltransferase (NNMT) in schizophrenia: genetic association and decreased frontal cortex mRNA levels. Int J Neuropsychopharmacol. 2011; 15(6):727-37. DOI: 10.1017/S1461145711001179. View

Campagna R, Cecati M, Pozzi V, Fumarola S, Pompei V, Milanese G . Involvement of transforming growth factor beta 1 in the transcriptional regulation of nicotinamide N-methyltransferase in clear cell renal cell carcinoma. Cell Mol Biol (Noisy-le-grand). 2018; 64(7):51-55. View

Campagna R, Mateuszuk L, Wojnar-Lason K, Kaczara P, Tworzydlo A, Kij A . Nicotinamide N-methyltransferase in endothelium protects against oxidant stress-induced endothelial injury. Biochim Biophys Acta Mol Cell Res. 2021; 1868(10):119082. DOI: 10.1016/j.bbamcr.2021.119082. View

10.

Campagna R, Salvolini E, Pompei V, Pozzi V, Salvucci A, Molinelli E . Nicotinamide N-methyltransferase gene silencing enhances chemosensitivity of melanoma cell lines. Pigment Cell Melanoma Res. 2021; 34(6):1039-1048. DOI: 10.1111/pcmr.12993. View

11.

Canto C, Menzies K, Auwerx J . NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015; 22(1):31-53. PMC: 4487780. DOI: 10.1016/j.cmet.2015.05.023. View

12.

CANTONI G . Methylation of nicotinamide with soluble enzyme system from rat liver. J Biol Chem. 1951; 189(1):203-16. View

13.

Cerami E, Gao J, Dogrusoz U, Gross B, Sumer S, Aksoy B . The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2(5):401-4. PMC: 3956037. DOI: 10.1158/2159-8290.CD-12-0095. View

14.

Chen C, Wang X, Huang X, Yong H, Shen J, Tang Q . Nicotinamide N-methyltransferase: a potential biomarker for worse prognosis in gastric carcinoma. Am J Cancer Res. 2016; 6(3):649-63. PMC: 4851844. View

15.

Chen D, Li L, Diaz K, Iyamu I, Yadav R, Noinaj N . Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide -Methyltransferase. J Med Chem. 2019; 62(23):10783-10797. PMC: 7296983. DOI: 10.1021/acs.jmedchem.9b01255. View

16.

Chlopicki S, Swies J, Mogielnicki A, Buczko W, Bartus M, Lomnicka M . 1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway. Br J Pharmacol. 2007; 152(2):230-9. PMC: 1978255. DOI: 10.1038/sj.bjp.0707383. View

17.

Couto J, Vulin M, Jehanno C, Coissieux M, Hamelin B, Schmidt A . Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer. EMBO J. 2023; 42(13):e112559. PMC: 10308372. DOI: 10.15252/embj.2022112559. View

18.

Cui Y, Zhang L, Wang W, Ma S, Liu H, Zang X . Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/β-catenin pathway. Mol Cell Biochem. 2019; 460(1-2):93-103. DOI: 10.1007/s11010-019-03573-0. View

19.

Cui Y, Yang D, Wang W, Zhang L, Liu H, Ma S . Nicotinamide N-methyltransferase decreases 5-fluorouracil sensitivity in human esophageal squamous cell carcinoma through metabolic reprogramming and promoting the Warburg effect. Mol Carcinog. 2020; 59(8):940-954. DOI: 10.1002/mc.23209. View

20.

Cuomo R, Dattilo M, Pumpo R, Capuano G, Boselli L, Budillon G . Nicotinamide methylation in patients with cirrhosis. J Hepatol. 1994; 20(1):138-42. DOI: 10.1016/s0168-8278(05)80480-5. View