Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Nicotinamide adenine dinucleotide (NAD) is best known as an essential cofactor of biochemical reactions. In addition, it is involved in the regulation of virtually all major cellular events. These NAD-dependent regulatory functions are mediated by enzymes (e.g., sirtuins, poly–adenosine -diphosphate [ADP] ribose polymerases, ADP-ribosyl cyclases) that cleave the molecule to liberate nicotinamide (Nam). We show that diversification of NAD-dependent signaling in Deuterostomia was accompanied by an optimization of NAD biosynthesis to ensure efficient high-affinity recycling of Nam into NAD through Nam phosphoribosyltransferase (NamPT). In addition, a Nam N-methyltransferase (NNMT) emerged, which facilitates high NAD-dependent signaling turnover by preventing accumulation of inhibitory Nam. This unexpected kinetic interplay between NamPT and NNMT needs to be considered in therapeutic strategies targeting these enzymes