# Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention
## 1 Introduction  
Nicotinamide (NAM) is an amide form of vitamin B3, a semi-essential vitamin. Many foods, including meat, fish, eggs, legumes, mushrooms, nuts, and grains contain NAM. However, NAM is also de novo synthetized (Figure 1) by tryptophan metabolism [1]. After ingestion, NAM is readily absorbed from the gastro-intestinal tract and widely distributed in the body tissues [2]. NAM is methylated in the liver to 1-methyl-NAM (MNA) by NAM-\(N\)-methyltransferase, and then oxidized to l-methyl-2-pyridone-5-carboxamide (2-Pyr) and l-methyl-4-pyridone-5-carboxamide (4-Pyr) (Figure 1). The major urinary metabolites are MNA and 2-Py, accounting for 20%-35% and 45%-60%, respectively [2]. Vitamin B3 deficiency affects tissues that need high cellular energy, such as brain, gut and skin causing pellagra. The main features of pellagra (photosensitive dermatitis, diarrhea, and dementia) are prevented by daily NAM intake of 15-20 mg from dietary sources [1; 3; 4]. NAM is the precursor of nicotinamide adenine dinucleotide (NAD+) (Figure 1), an essential co-enzyme of redox reactions for adenosine triphosphate (ATP) production and for several other metabolic processes [2; 3; 4]. Beyond its role as co-enzyme, NAD+ may act as substrate for specific NAD+-consuming enzymes and influences cellular responses to genomic damage through different mechanisms [2; 4; 5]. Figure 1: Nicotinamide (NAM) and Nicotinamide Adenine Dinucleotide (NAD+) metabolism. One source of NAM is the diet, via intake of eggs, meat, fish, and mushrooms. After ingestion, NAM is readily absorbed from the gastro-intestinal tract and widely distributed in the body tissues. NAM is the precursor of nicotinamide adenine dinucleotide (NAD+) that is an essential co-enzyme of redox reactions for adenosine triphosphate (ATP) production and for several metabolic processes. NAM is converted to NAD+ through the salvage pathway that represents the major route of NAD+ biosynthesis in mammals. NAM phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme that catalyzes the first step in the biosynthesis of NAM mononucleotide (NMN) from NAM. Subsequently, the NMN adenylyltransferases (NMNATs) utilize ATP for the generation of NAD+. This coenzyme may be directly converted from NADP+ by NAD kinase (NADK). NMN can be also synthetized by nicotinic acid (NA) and NAM riboside (NR). Since NAD+ acts as substrate for specific NAD+-consuming enzymes, NAM is also generated as by-product by these reactions and recycled in the salvage pathway. Specifically, the cyclic ADP-ribose synthases (cADPRSs) hydrolyze NAD+ to NAM. Poly (ADP-ribose) polymerases (PARPs), use NAD+ as a co-substrate to PARylate target proteins (Subs), generating NAM. The deacetylation of specific substrates (Subs) by Sirtuins (SIRTs), which are NAD+ dependent enzymes, generates NAM. NAM is removed from recycling by degradation that thus indirectly affects NAD+ levels. NAM is methylated to 1-methyl-NAM (MNA) by NAM-N-methyltransferasease (NNMT) and then oxidized to l-methyl-2-pyridone-5-carboxamide (2-Pyr) and l-methyl-4-pyridone-5-carboxamide (4-Pyr). A two-step salvage pathway (Figure 1), which converts NAM to NAD+, represents the major route of NAD+ biosynthesis in mammals. NAM phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme that catalyzes the first step in the biosynthesis of NAM mononucleotide (NMN) from NAM and ATP. Subsequently, the NMN adenylyltransferases (NMNATs) utilize ATP for the generation of NAD+. This coenzyme may be directly converted in NADP+ by NAD kinase [3; 4]. NAD+ can be also synthetized by other precursors, such as nicotinic acid (NA) and NAM riboside (NR) (Figure 1). NAD+ status is critical in preserving genomic stability. Tissues with high cellular turnover, such as skin, require higher doses of NAD+ to counteract genomic insults [6]. Low NAD+ level increases sun sensitivity in the skin. Indeed, it alters p53 expression, induces genomic instability, and reduces survival following exposure to solar-simulated (ss) UV radiation [3; 6].