Figure 3.

Schematic representation of distinct catabolic pathways. (1) NAD is hydrolyzed onto nicotinamide mononucleotide via the action of specific pyrophosphatases belonging to Nudix (nucleoside diphosphate linked to moiety X) family. (2) Nicotinamide mononucleotide is then dephosphorylated by Isn1 and Sdt1 cytosolic nucleotidases, which release the corresponding riboside cleaved to nicotinamide by a purine nucleoside phosphorylase (PNP) (3). Alternatively, NAD becomes a substrate of sirtuins (4), ADP-ribosyltransferases (ARTC) (5) and diphtheria toxin-like ADP-ribosyltransferases (ARTD) (6). Nicotinamide can be either re-converted to NAD by specific enzymes (7) (see also Figure 2) or methylated by nicotinamide-N-methyl transferase (NNMT) to N¹-methylnicotinamide (8) that, in turn, (9) is oxidized to N¹-methyl-4-pyridone-3-carboxamide (4-Py) and N¹-methyl-2-pyridone-5-carboxamide (2-Py) by aldehyde oxidases. 2-OAADPr: O-acetyl-ADP ribose; NAMPT: nicotinamide phosphoribosyltransferase; NMNAT: nicotinamide/nicotinic acid-mononucleotide-adenylyltransferase; SAH: S-adenosylhomocysteine; SAM: S-adenosyl-methionine.