The copper-sensing transcription factor Mac1, the histone deacetylase Hst1, and nicotinic acid regulate de novo NAD+ biosynthesis in budding yeast

• DOI: 10.1074/jbc.ra118.006987
• Publication Date: 2019-02-14T00:45:26Z
• Authors: Christol James Th...; Trevor Croft; Padmaja Venkatakr...; Benjamin Groth; Gagandeep Dhugga; Timothy Cater; Su-Ju Lin
• Keywords: 570; Biochemistry & Molecular Biology; Biomedical and clinical sciences; Saccharomyces cerevisiae Proteins; 610; metal sensing; Saccharomyces cerevisiae; Medical and Health Sciences; Niacin; Industrial Biotechnology; yeast genetics; Mice; Sirtuin 2; cell metabolism; NAD+ biosynthesis; Genetics; Animals; nicotinic acid; nicotinamide adenine dinucleotide; epigenetics; Nuclear Proteins; Biological Sciences; Quinolinic Acid; NAD plus biosynthesis; NAD; Biological sciences; Chemical sciences; histone deacetylase; Chemical Sciences; metabolic regulation; yeast metabolism; gene regulation; Copper; Transcription Factors

NADH (NAD+) is an essential metabolite involved in various cellular biochemical processes. The regulation of NAD+ metabolism incompletely understood. Here, using budding yeast (Saccharomyces cerevisiae), we established intermediate-specific genetic system to identify factors that regulate the de novo branch biosynthesis. We found a mutant strain (mac1Δ) lacking Mac1, copper-sensing transcription factor activates copper transport genes during deprivation, exhibits increases quinolinic acid (QA) production and levels. Similar phenotypes were also observed hst1Δ strain, deficient NAD+-dependent histone deacetylase Hst1, which inhibits synthesis by repressing BNA gene expression when abundant. Interestingly, mac1Δ mutants shared similar metabolism-related profile, deleting either MAC1 or HST1 de-repressed genes. ChIP experiments with BNA2 promoter indicated Mac1 works Hst1-containing repressor complexes silence expression. connection suggested stress affects synthesis, show induces both QA production. Moreover, nicotinic inhibited through Hst1-mediated repression, hindered reuptake extracellular QA, thereby reduced synthesis. In summary, have identified characterized novel homeostasis factors. These findings will expand our understanding molecular basis metabolism.