Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation

Abstract

Background The abundance of energy metabolites is intimately interconnected with the activity of chromatin-modifying enzymes in order to guarantee the finely tuned modulation of gene expression in response to cellular energetic status. Metabolism-induced epigenetic gene regulation is a key molecular axis for the maintenance of cellular homeostasis, and its deregulation is associated with several pathological conditions. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM), directly linking one-carbon metabolism with a cell's methylation balance and nicotinamide adenine dinucleotide (NAD + ) levels. NNMT expression and activity are regulated in a tissue-specific-manner, and the protein can act either physiologically or pathologically depending on its distribution. While NNMT exerts a beneficial effect by regulating lipid parameters in the liver, its expression in adipose tissue correlates with obesity and insulin resistance. NNMT upregulation has been observed in a variety of cancers, and increased NNMT expression has been associated with tumor progression, metastasis and worse clinical outcomes. Accordingly, NNMT represents an appealing druggable target for metabolic disorders as well as oncological and other diseases in which the protein is improperly activated. Scope of review This review examines emerging findings concerning the complex NNMT regulatory network and the role of NNMT in both NAD metabolism and cell methylation balance. We extensively describe recent findings concerning the physiological and pathological regulation of NNMT with a specific focus on the function of NNMT in obesity, insulin resistance and other associated metabolic disorders along with its well-accepted role as a cancer-associated metabolic enzyme. Advances in strategies targeting NNMT pathways are also reported, together with current limitations of NNMT inhibitor drugs in clinical use. Major conclusions NNMT is emerging as a key point of intersection between cellular metabolism and epigenetic gene regulation, and growing evidence supports its central role in several pathologies. The use of molecules that target NNMT represents a current pharmaceutical challenge for the treatment of several metabolic-related disease as well as in cancer.

The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes

“…The transcription factories housing the broad epigenetic domain and its interactome would have a high demand for energetic metabolites such as ATP, S-adenosyl methionine, acetyl-CoA, NAD, and α-ketoglutarate. Disturbance in the availability of these metabolites in the diet or as a consequence of disease may impact the expression of genes with the broad epigenetic domain [ 134 , 135 ]. Exploring the orchestration of the metabolites and epigenetic players in the formation and maintenance of transcription factories/hubs with genes with a broad epigenetic domain and their interactome of enhancers and super-enhancers is a prerequisite to understanding cell differentiation and disease.…”

Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies

“…Follow-up studies Nicotinamide N-methyltransferase (NNMT) is an enzyme that ties one carbon metabolism with the methylation balance and nicotinamide adenine dinucleotide (NAD+) levels of the cell by catalysing nicotinamide (NAM) methylation via SAM. Elevated NNMT expression in murine white adipose tissue (WAT) has been associated with obesity and insulin resistance, whereas WAT NNMT knockout was protective [153,154]. It is already known that the dose of metformin may differentially affect cellular NAD+ levels [155]; however, whether metformin impacts NNMT expression requires further investigation.…”

Fibrinolytic System and Cancer: Diagnostic and Therapeutic Applications

“…SAM is a pleiotropic molecule and utilized as a cofactor by many enzymes, some of which are involved in tumorigenesis. For example, nicotinamide N-methyltransferase (NNMT) uses endogenous SAM to mediate its enzymatic activity [ 81 ]. Overexpression of NNMT has been seen in many cancers [ 82 , 83 , 84 ].…”