# Defining NAD(P)(H) catabolism
## 3 Non-Ribosylated Catabolites of NAD(P)(H)
Another methylated vitamin B3 derivative is trigonelline (Table 1). Trigonelline (Figure 4) is methylated nicotinic acid. Although not a known catabolite or precursor of NAD or NAAD, trigonelline is thought to have beneficial effects on human health. It is generated in plants by methylation of nicotinic acid, a process that mammalian NMNT is not known to carry out [94]. It is found in greater abundance in coffee beans, for which  
Figure 3: Known catabolites resulting from nicotinamide (NAM) catabolism. NA: nicotinic acid; NUA: nicotinic acid; Me-6 PY: \(N\)-methyl-3-carboxylate-6-pyridone; Me-4 PY: \(N\)-methyl-3-carboxylate-4-pyridone; NAM-N-oxide: nicotinamide \(N\)-oxide; NNMT: nicotinamide \(N\)-methyltransferase. the levels increase upon torrefraction [95]. Trigonelline is not perceived to be a mammalian metabolite. However, it is often found in urinary specimens of coffee drinkers. A risk assessment of trigonelline consumption was recently conducted [96]. Although there was no evidence of adverse effects after acute exposure, no conclusion could be drawn on chronic exposure to isolated trigonelline due to the lack of data. Yet, trigonelline ingested as a component of coffee or coffee by-products was concluded to be safe for human health [96]. The effects of trigonelline on the overall levels of NAD(P)(H) and its precursors in biospecimens remain unexplored. While these examples of correlations between excess nicotinamide and diseases can be potentially ascribed to a modulation in the intracellular abundance of SAM and NAD\({}^{+}\), the full picture of induced dysfunction concerning excess nicotinamide is not yet acquired. Therefore, the need for monitoring the NAD\({}^{+}\) catholites of nicotinic acid and nicotinamide more systematically is warranted. For example, urinary and serum nicotinic acid inform how well nicotinic acid is scavenged from microbial sources and used to generate systemic NAD\({}^{+}\) via the Preiss-Handler pathway. Additionally, the accumulation of circulating and excreted methylated nicotinamide catabolites informs how much NAD\({}^{+}\) consumption is required to maintain cellular homeostasis, which informs on the activity of sirtius, ARTs, SARM1, BST1, and CD38. Similarly, the relative abundance of NAM-N-oxide, \(N\)-Me-NAM, and NUA compared with circulating NAM and NA is an indicator of the relative contribution made by the salvage and the Preiss-Handler pathways while maintaining intracellular NAD\({}^{+}\) pools. Overall, a relative abundance of nicotinic acid, nicotinamide N-oxide, and methyl-incotinamide catabolites offer a window into systemic NAD\({}^{+}\) metabolism and the use of its precursors for NAD(P)(H) level maintenance. Oxidation of NAD(P)(H) primary catabolites: Among metabolic reactions, the oxidation of heteroamoratics accounts for the most predominant bioconversion in drug metabolism. Degradation of NAD\({}^{+}\) metabolites through oxidation is therefore common and these species are the most encountered NAD\({}^{+}\) catabolites in biospecimens [97]. The position of the resulting carbonyl with respect to the carboxamide of nicotinamide indicates the isomer formed upon oxidation. In mice, the 6 and the 4 isomers (as depicted in Figure 3) are the most frequently found isomers. In humans, the isomer Me-6-PY is most often reported as being the only detected isomer, and thus thought to be the predominant N-Me-NAM catabolite. Critically, Me-6-PY (Figure 3) is most frequently reported in the literature as 2-PY or Me-2-PY. This later nomenclature is particularly confusing since non-methylated oxidized nicotinamide, also labeled PY, can be detected in biological samples, although their levels are substantially lower than that of the methylated species. Furthermore, the nomenclature 2 PY (aka. 6-Me-PY) positions the carboxamide of nicotinamide at the C5 of the pyridine ring. In nicotinamide, the carboxamide is located at the C3 of the pyridine ring.