Dual control of NAD + synthesis by purine metabolites in yeast

Elife. 2019 Mar 12;8:e43808. 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.

Keywords: S. cerevisiae; chromosomes; gene expression; homeostasis; metabolic regulation; yeast genetics.

MeSH terms

  • Adenine / chemistry
  • Adenosine Triphosphate / chemistry
  • Biomass
  • Chromatography, Liquid
  • Fungal Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Genotype
  • Homeodomain Proteins / metabolism
  • Homeostasis
  • NAD / biosynthesis*
  • Niacin / chemistry
  • Nicotinamide-Nucleotide Adenylyltransferase / genetics
  • Nicotinamide-Nucleotide Adenylyltransferase / metabolism*
  • Purines / chemistry*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism

Substances

  • BAS1 protein, S cerevisiae
  • Fungal Proteins
  • Homeodomain Proteins
  • PHO2 protein, S cerevisiae
  • Purines
  • Saccharomyces cerevisiae Proteins
  • Trans-Activators
  • Transcription Factors
  • NAD
  • Niacin
  • Adenosine Triphosphate
  • NMA1 protein, S cerevisiae
  • Nicotinamide-Nucleotide Adenylyltransferase
  • Adenine

Associated data

  • GEO/GSE13275
  • GEO/GSE29324

Grant support

The authors declare that there was no funding for this work