In all organisms biomolecules play a vital role to enable proper cellular metabolism. Alteration of metabolite homoeostasis disrupts the physiology of cells, leading to various diseases [DeBerardinis and Thompson (2012) Cell, 148, 1132–1144]. Recent studies advances our understanding that some metabolites are not only involved in cellular metabolism, but also have other molecular functions. It has become evident that similar to multifunctional ‘moonlighting proteins’, ‘moonlighting metabolites’ also exists. One clear example is nicotinamide adenine dinucleotide (NAD). NAD is a ubiquitous molecule with a well-known function in many metabolic reactions, but it also has become clear that NAD is involved in the regulation of sirtuins. Sirtuins play a role in cancer, diabetes, and cardiovascular, neurodegenerative and other diseases [Donmez and Outeiro (2013) EMBO Mol. Med. 5, 344–352] and the deacetylation capacity of sirtuin proteins is NAD-dependent. This direct role of NAD in age-related diseases could not be anticipated when NAD was initially discovered as a metabolic cofactor [Donmez and Outeiro (2013) EMBO Mol. Med. 5, 344–352; Mouchiroud et al. (2013) Crit. Rev. Biochem. Mol. Biol. 48, 397–408]. Recent findings now also indicate that CoA (coenzyme A), another metabolic cofactor, can be considered as being more than ‘just’ a metabolic cofactor, and altered CoA levels lead to severe and complex effects.

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