Seminars

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite for cellular redox chemistry, metabolism, and signaling. NAD+ metabolism is also an emerging therapeutic target for a number of human disorders associated with aberrance NAD+ metabolism. Although administration of NAD+ precursors such as nicotinamide mononucleotide (NMN), nicotinamide (NAM) and nicotinamide riboside (NR) has been shown to ameliorate NAD+ deficiencies in several systems, molecular mechanisms underlying these beneficial effects remain incompletely understood. Studying NAD+ homeostasis is complicated by the complex and dynamic flexibility of NAD+ precursors as well as the lack of sensitive and specific genetic screen systems. Using budding yeast (Saccharomyces cerevisiae), we have established various NAD+ precursor-specific reporter systems to screen and study mutants with altered NAD+ metabolism. Our studies have uncovered novel NAD+ homeostasis factors including components of nutrient signaling pathways, NAD+ intermediate transporters, NAD+ metabolic enzymes, and factors involved in protein modification and chromatin remodeling. Here, I will first present our recent studies of how N-terminal protein acetylation modulates the levels of a rate-liming enzyme in NAD+ biosynthesis. Next, I will discuss a cross-regulation of the de novo NAD+ biosynthesis by the copper-sensing transcription factor Mac1, which works with the NAD+-dependent Hst1 repressor complex to regulate gene expression. Our studies may contribute to the understanding of the molecular basis and inter-connection of multiple NAD+ metabolic pathways, which is also important for the development of disease-specific therapeutic strategies.