Dual control of NAD+ synthesis by purine metabolites in yeast.

Benoît Pinson,Johanna Ceschin,Bertrand Daignan-Fornier,Christelle Saint-Marc

doi:10.7554/elife.43808

Abstract

Metabolism is a highly integrated process resulting in energy and biomass production. While individual metabolic routes are well characterized, the mechanisms ensuring crosstalk between pathways are poorly described, although they are crucial for homeostasis. Here, we establish a co-regulation of purine and pyridine metabolism in response to external adenine through two separable mechanisms. First, adenine depletion promotes transcriptional upregulation of the de novo NAD+ biosynthesis genes by a mechanism requiring the key-purine intermediates ZMP/SZMP and the Bas1/Pho2 transcription factors. Second, adenine supplementation favors the pyridine salvage route resulting in an ATP-dependent increase of intracellular NAD+. This control operates at the level of the nicotinic acid mononucleotide adenylyl-transferase Nma1 and can be bypassed by overexpressing this enzyme. Therefore, in yeast, pyridine metabolism is under the dual control of ZMP/SZMP and ATP, revealing a much wider regulatory role for these intermediate metabolites in an integrated biosynthesis network.

Highlights

Nicotinamide adenine dinucleotide (NAD+/NADH) is a coenzyme mediating hydrogen exchange in a myriad of metabolic reactions and a co-substrate for several enzymes including the sirtuin protein deacetylases, Poly (ADP-ribose) polymerase (PARP), and the cyclic ADP-ribosesynthases (Verdin, 2015)
We showed concomitant increase of several NAD+ de novo synthesis intermediates when adenine was absent and an enhanced decrease of the precursor tryptophan, establishing that the de novo pathway is upregulated under these conditions (Figure 8E)
It should be stressed that synthesis of NaMN from nicotinic acid is at the cost of an ATP molecule while synthesis of NaMN from tryptophan does not consume ATP (Figure 1A)

Summary

Introduction

Nicotinamide adenine dinucleotide (NAD+/NADH) is a coenzyme mediating hydrogen exchange in a myriad of metabolic reactions and a co-substrate for several enzymes including the sirtuin protein deacetylases, Poly (ADP-ribose) polymerase (PARP), and the cyclic ADP-ribose (cADPR)synthases (Verdin, 2015). NAD+ was found to decline with ageing, possibly through limitation of recycling or increased consumption via PARP (Imai and Guarente, 2014). This decline can be reversed by supplementation with nicotinamide (NAM), its riboside (NR) or mono-nucleotide (NMN) derivatives, that can result in health improvement and/or extended lifespan, the underneath mechanisms are not fully understood (Mitchell et al, 2018; Rajman et al, 2018; Yoshino et al, 2018). Orthologs of PARP and cADPR synthases have not been identified, but the Sir sirtuin proved to be a key player in conveying NAD+ status as a signal in biological processes such as gene expression silencing (Moazed, 2001), ageing (Lin and Guarente, 2003) or cell size homeostasis (Moretto et al, 2013)

Methods

Results

Conclusion