HGNC Approved Gene Symbol: NNMT
Cytogenetic location: 11q23.2 Genomic coordinates (GRCh38): 11:114,257,806-114,313,536 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.2 | Homocysteine plasma level | 600008 | 2 |
Nicotinamide N-methyltransferase (EC 2.1.1.1) catalyzes the N-methylation of nicotinamide and other pyridines (summary by Aksoy et al., 1994).
Human liver NNMT activity has a bimodal frequency distribution, an observation that raises the possibility that this enzyme activity may be regulated by a genetic polymorphism. Such a polymorphism could have functional implications for individual differences in drug and xenobiotic toxicity. As a first step toward testing that hypothesis, Aksoy et al. (1994) isolated a cDNA for human liver NNMT that was 969 bp long, with a 792-bp open reading frame that encoded a 264-amino acid protein with a calculated molecular mass of 29,600 Da. Aksoy et al. (1994) suggested that the cDNA could be used to study the molecular basis of individual differences in enzyme activity in humans.
Using a cosmid clone from a human chromosome 11-specific genomic library, Aksoy et al. (1995) determined that the human NNMT gene is approximately 16.5 kb in length and consists of 3 exons and 2 introns. Transcription initiation for the NNMT gene occurs 105 to 109 bp 5-prime upstream from the cDNA translation initiation codon, as determined by both primer extension and 5-prime rapid amplification of cDNA ends.
Kraus et al. (2014) used DNA array analyses to demonstrate that NNMT is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue from adipose-specific Glut4 (138190)-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD+, an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux, including synthesis, catabolism, and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC; 165640) and spermidine-spermine N(1)-acetyltransferase (SSAT1; 313020) and by polyamine oxidase (PAOX; 615853) and has a major role in energy metabolism. Kraus et al. (2014) reported that Nnmt expression is increased in white adipose tissue and liver of obese and diabetic mice. Nnmt knockdown in white adipose tissue and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD+ levels and upregulates ODC and SSAT1 activity as well as expression, owing to the effects of NNMT on histone H3 lysine-4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT1-, and PAOX-dependent manner. Thus, Kraus et al. (2014) concluded that NNMT is a novel regulator of histone methylation, polyamine flux, and NAD+-dependent SIRT1 (604479) signaling, and is a unique and attractive target for treating obesity and type 2 diabetes.
Eckert et al. (2019) developed a label-free proteomic workflow to analyze as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from both the tumor and stromal compartments of ovarian cancer (see 167000). The tumor proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase NNMT and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation, and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumor stroma. Eckert et al. (2019) concluded that NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma.
Aksoy et al. (1995) localized the NNMT gene to chromosome 11 by performing PCR with human/rodent hybrid cell DNA as template and with both intron- and exon-based primers. By fluorescence in situ hybridization, they mapped NNMT to chromosome 11q23.1.
Homocysteine (Hcy) plasma level is an independent risk marker for venous thrombosis, myocardial infarction, stroke, congestive heart failure, osteoporotic fractures, and Alzheimer disease (AD; 104300). Hcy levels are determined by the interaction of genetic and environmental factors. The 677C-T polymorphism in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR; 607093.0003) has consistently been associated with plasma Hcy levels. Souto et al. (2005) conducted a genomewide linkage scan for genes affecting variation in plasma Hcy levels in 398 patients from 21 extended Spanish families. The strongest linkage signal (lod score = 3.01; genomewide p = 0.035) was found on 11q23 in the vicinity of the NNMT gene, which is involved in the metabolism of homocysteine. Haplotype analyses of 10 SNPs within this gene identified 1 haplotype associated with plasma Hcy levels (p = 0.0003). Souto et al. (2005) concluded that the NNMT gene may be a major genetic determinant of plasma homocysteine levels in Spanish families and that since this gene encodes an enzyme involved in homocysteine synthesis, the finding would be consistent with known biochemical pathways.
Aksoy, S., Brandriff, B. F., Ward, A., Little, P. F. R., Weinshilboum, R. M. Human nicotinamide N-methyltransferase gene: molecular cloning, structural characterization and chromosomal localization. Genomics 29: 555-561, 1995. [PubMed: 8575745] [Full Text: https://doi.org/10.1006/geno.1995.9966]
Aksoy, S., Szumlanski, C. L., Weinshilboum, R. M. Human liver nicotinamide N-methyltransferase: cDNA cloning, expression, and biochemical characterization. J. Biol. Chem. 269: 14835-14840, 1994. [PubMed: 8182091]
Eckert, M. A., Coscia, F., Chryplewicz, A., Chang, J. W., Hernandez, K. M., Pan, S., Tienda, S. M., Nahotko, D. A., Li, G., Blazenovic, I., Lastra, R. R., Curtis, M., Yamada, S. D., Perets, R., McGregor, S. M., Andrade, J., Fiehn, O., Moellering, R. E., Mann, M., Lengyel, E. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature 569: 723-728, 2019. [PubMed: 31043742] [Full Text: https://doi.org/10.1038/s41586-019-1173-8]
Kraus, D., Yang, Q., Kong, D., Banks, A. S., Zhang, L., Rodgers, J. T., Pirinen, E., Pulinilkunnil, T. C., Gong, F., Wang, Y., Cen, Y., Sauve, A. A., Asara, J. M., Peroni, O. D., Monia, B. P., Bhanot, S., Alhonen, L., Puigserver, P., Kahn, B. B. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508: 258-262, 2014. [PubMed: 24717514] [Full Text: https://doi.org/10.1038/nature13198]
Souto, J. C., Blanco-Vaca, F., Soria, J. M., Buil, A., Almasy, L., Ordonez-Llanos, J., Martin-Campos, J. M., Lathrop, M., Stone, W., Blangero, J., Fontcuberta, J. A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT Project. Am. J. Hum. Genet. 76: 925-933, 2005. [PubMed: 15849667] [Full Text: https://doi.org/10.1086/430409]