The functional cofactors derived from vitamin B3 are nicotinamide adenine dinucleotide (NAD⁺), its phosphorylated form, nicotinamide adenine dinucleotide phosphate (NADP⁺) and their reduced forms (NAD(P)H). These cofactors, together referred as the NAD(P)(H) pool, are intimately implicated in all essential bioenergetics, anabolic and catabolic pathways in all forms of life. This pool also contributes to post-translational protein modifications and second messenger generation. Since NAD⁺ seats at the cross-road between cell metabolism and cell signaling, manipulation of NAD⁺ bioavailability through vitamin B3 supplementation has become a valuable nutritional and therapeutic avenue. Yet, much remains unexplored regarding vitamin B3 metabolism. The present review highlights the chemical diversity of the vitamin B3-derived anabolites and catabolites of NAD⁺ and offers a chemical perspective on the approaches adopted to identify, modulate and measure the contribution of various precursors to the NAD(P)(H) pool.

Nicotinamide adenine dinucleotide (NAD⁺) and its reduced form (NADH) are coenzymes employed in hundreds of metabolic reactions. NAD⁺ also serves as a substrate for enzymes such as sirtuins, poly(ADP-ribose) polymerases (PARPs) and ADP-ribosyl cyclases. Given the pivotal role of NAD(H) in health and disease, studying NAD⁺ metabolism has become essential to monitor genetic- and/or drug-induced perturbations related to metabolic status and diseases (such as ageing, cancer or obesity), and its possible therapies. Here, we present a strategy based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), for the analysis of the NAD⁺ metabolome in biological samples. In this method, hydrophilic interaction chromatography (HILIC) was used to separate a total of 18 metabolites belonging to pathways leading to NAD⁺ biosynthesis, including precursors, intermediates and catabolites. As redox cofactors are known for their instability, a sample preparation procedure was developed to handle a variety of biological matrices: cell models, rodent tissues and biofluids, as well as human biofluids (urine, plasma, serum, whole blood). For clinical applications, quantitative LC-MS/MS for a subset of metabolites was demonstrated for the analysis of the human whole blood of nine volunteers. Using this developed workflow, our methodology allows studying NAD⁺ biology from mechanistic to clinical applications.

The β-anomeric form of nicotinamide riboside (NR⁺) is a precursor for nicotinamide adenine dinucleotide (NAD⁺), a redox cofactor playing a critical role in cell metabolism. Recently, it has been demonstrated that its chloride salt (NR⁺Cl⁻) has beneficial effects, and now NR⁺Cl⁻ is available as a dietary supplement. Syntheses and studies of analogues and derivatives of NR⁺ are of high importance to unravel the role of NR⁺ in biochemical processes in living cells and to elaborate the next generation of NR⁺ derivatives and conjugates with the view of developing novel drug and food supplement candidates. This review provides an overview of the synthetic approaches, the chemical properties, and the structural and functional modifications which have been undertaken on the nicotinoyl riboside scaffold.

A number of new ionic vinyl monomers composed of 1-vinylimidazolium cation with diethoxy- and dihydroxyphosphoryl groups and various anions—Br−, (CN)2N−, and (CF3SO2)2N−—are synthesized. The...

As catabolites of nicotinamide possess physiological relevance, pyridones are often included in metabolomics measurements and associated with pathological outcomes in acute kidney injury (AKI). Pyridones are oxidation products of nicotinamide, its methylated form, and its ribosylated form. While they are viewed as markers of over-oxidation, they are often wrongly reported or mislabeled. To address this, we provide a comprehensive characterization of these catabolites of vitamin B3, justify their nomenclature, and differentiate between the biochemical pathways that lead to their generation. Furthermore, we identify an enzymatic and a chemical process that accounts for the formation of the ribosylated form of these pyridones, known to be cytotoxic. Finally, we demonstrate that the ribosylated form of one of the pyridones, the 4-pyridone-3-carboxamide riboside (4PYR), causes HepG3 cells to die by autophagy; a process that occurs at concentrations that are comparable to physiological concentrations of this species in the plasma in AKI patients.