Reconstructing eukaryotic NAD metabolism

Abstract

In addition to its well-known role as a coenzyme in oxidation-reduction reactions, the distinct role of NAD as a precursor for molecules involved in cell regulation has been clearly established. The involvement of NAD in these regulatory processes is based on its ability to function as a donor of ADP-ribose; NAD synthesis is therefore required to avoid depletion of the intracellular pool. The rising interest in the biosynthetic routes leading to NAD formation and the highly conserved nature of the enzymes involved prompted us to reconstruct the NAD biosynthetic routes operating in distinct eukaryotic organisms. The evidence obtained from biochemical and computational analysis provides a good example of how complex metabolic pathways may evolve. In particular, it is proposed that the development of several NAD biosynthetic routes during evolution has led to partial functional redundancy, allowing a given pathway to freely acquire novel functions unrelated to NAD biosynthesis.

The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

“…4B). Consistent with the biochemical characteristics of these (26,61). Pnc1, Npt1, Nma1, Nma2, and Qns1 are nicotinamidase, nicotinic acid phosphoribosyltransferase, nicotinic acid mononucleotide adenylyltransferase 1 and 2, and NAD synthetase, respectively.…”

“…Pnc1, Npt1, Nma1, Nma2, and Qns1 are nicotinamidase, nicotinic acid phosphoribosyltransferase, nicotinic acid mononucleotide adenylyltransferase 1 and 2, and NAD synthetase, respectively. This pathway is also conserved in C. elegans, Drosophila, and other invertebrates (26). B, NAD biosynthesis from nicotinamide and nicotinic acid in mammals is shown.…”

“…3). Organisms that do not have Nampt, such as Saccharomyces cerevisiae, C. elegans, and Drosophila, unanimously carry a gene encoding nicotinamidase (26,47), which converts nicotinamide to nicotinic acid, the main precursor for NAD biosynthesis in those organisms (Fig. 1A).…”

“…In yeast, PNC1 encodes nicotinamidase and enhances the function of Sir2 in response to a variety of stresses (23,24). Since no obvious homologs of Pnc1 have been found in vertebrates (26), the presence of Nampt, which allows a more direct pathway for NAD biosynthesis from nicotinamide (Fig. 1B), clearly distinguishes the vertebrate NAD biosynthesis and its relationship with Sir2.…”

“…1). Vertebrates lack any obvious homolog of the yeast nicotinamidase (Pnc1) (26), and the recycling of nicotinamide into NAD is more direct (Fig. 1B).…”