Learning from evolution – from comparative genomics to physiology

Ines Heiland

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor required for a large number of metabolic reactions. In addition, it plays an important role in signaling processes. All living organisms have one or several biosynthesis routes for NAD these can be roughly separated into de novo synthesis from amino acids (either aspartate or tryptophan) or biosynthesis from more complex precursors such as vitamin B3 (niacin and nicotinamide) also called salvage pathways as they are used to recycle degradation products of NAD. Looking at the evolution of these pathways we see that there is a clear transition for the de novo synthesis pathway that is based on aspartate in most bacteria and archaea while it is dependent on tryptophan in eukaryotes. In contrast, there is no clear evolutionary pattern for the salvage pathways beside the fact that one of them is lost in higher metazoan. Therefore, we investigated the phylogenetic distribution of the salvage pathways and recognized a selection for one of them in extremophile organisms. On the other hand we see that the loss of this pathways in eukaryotes goes along with additional pathway changes, like the development of a recycling enzyme with very high affinity for nicotinamide (Nam) that coincide with the diversification of NAD dependent signaling reactions that produce Nam.

Using mathematical models of the pathway we show e.g. that the diversification is favored in a system with a high affinity recycling pathway coupled to a degradation pathway that removes excess precursors to prevent product inhibition of signaling reactions. As changes in the expression of these enzymes are found in many ageing related diseases our observation are of high physiological relevance and should be considered for the development of related treatment strategies.