The Evolutionary Portrait of Metazoan NAD Salvage

Abstract

Nicotinamide Adenine Dinucleotide (NAD) levels are essential for cellular homeostasis and survival. Main sources of intracellular NAD are the salvage pathways from nicotinamide, where Nicotinamide phosphoribosyltransferases (NAMPTs) and Nicotinamidases (PNCs) have a key role. NAMPTs and PNCs are important in aging, infection and disease conditions such as diabetes and cancer. These enzymes have been considered redundant since either one or the other exists in each individual genome. The co-occurrence of NAMPT and PNC was only recently detected in invertebrates though no structural or functional characterization exists for them. Here, using expression and evolutionary analysis combined with homology modeling and protein-ligand docking, we show that both genes are expressed simultaneously in key species of major invertebrate branches and emphasize sequence and structural conservation patterns in metazoan NAMPT and PNC homologues. The results anticipate that NAMPTs and PNCs are simultaneously active, raising the possibility that NAD salvage pathways are not redundant as both are maintained to fulfill the requirement for NAD production in some species.

Sirtuin Evolution at the Dawn of Animal Life

“…While the presence of both PNC1 and NAMPT has been demonstrated in multiple invertebrates ( Gossmann et al 2012 ; Carneiro et al 2013 ; Bockwoldt et al 2019 ), there remains a persistent notion that they regulate mutually exclusive pathways. Our study confirms that both genes were present in the last common ancestor of animals, demonstrated by their retention in living choanoflagellates and some sponges and ctenophores ( fig.…”

Sequence divergence and diversity suggests ongoing functional diversification of vertebrate NAD metabolism

“…Among the slowest evolving enzymes is also NAMPT, the rate-limiting enzyme of NAD biosynthesis [77,78] , which was believed to be only present in vertebrates until very recently. However there is accumulating evidence, that this enzyme is present in lower eukaryotes and has been lost several independent times in various non-vertebrate lineages [16,18] . However, enzymatic functionality of non-vertebrate NAMPT has yet to be shown.…”

“…1 ). From a phylogenetic perspective the occurrence of NAD biosynthetic enzymes is remarkably conserved across taxa [16] , with only a few exceptions [17,18] . However the diversification of vertebrates species is associated with an diversification of NAD degrading enzymes [16] .…”

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

“…We and others have shown earlier that the 2 NAD biosynthesis pathways starting from Nam (Fig. 1) coexist in some eukaryotes (36,39), as well as in some bacterial species (40). Why these pathways coexist in some organisms and over a very long evolutionary time frame, and why NADA nevertheless disappeared in vertebrates, is not known.…”