Abstract
The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly–adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT’s positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.
Highlights
Acquired resistance to anti-cancer agents is one of the major obstacles to the successful treatment of cancer patients [1,2]
Since distinct forms of NNMTregulated histone methylations direct a metabolic switch between cells residing in different phenotypic states, it is conceivable that metabolic reprogramming has a causative role, rather than being a mere consequence of acquisition of stem cell properties [81,82]
It is reasonable to hypothesize that a decline in H2 O2 production accompanies PPZ-mediated inhibition of aldehyde oxidase 1 (AOX1), and this mechanism should be considered as a possible contributor to activation of PP2A, as it was observed, but not properly explained, in Palachinamy’s study [76]
Summary
Acquired resistance to anti-cancer agents is one of the major obstacles to the successful treatment of cancer patients [1,2]. This metabolic pathway is, in humans, less efficient than in mice The reason for this is high activity of alpha-amino-beta-carboxy-muconatesemialdehyde decarboxylase (ACMSD), an enzyme which diverts alpha-amino-beta-carboxy-muconatesemialdehyde (ACMS), an intermediate metabolite in the kynurenine pathway, away from NAD+ synthesis by limiting its spontaneous cyclization into quinolinic acid (Figure 1) [21]. For this reason, humans utilize ~60–70 mg Trp to generate an equivalent amount of NAD+. Sci. 2021, 22, 5681 pha-amino-beta-carboxy-muconatesemialdehyde (ACMS), an intermediate metabolite in the kynurenine pathway, away from NAD+ synthesis by limiting its spontaneous cyclization into quinolinic acid (Figure 1) [21] For this reason, humans utilize ~60–70 mg.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
