Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae.
NAD(+) (nicotinamide adenine dinucleotide) is an essential cofactor involved in various biological processes including calorie restriction-mediated life span extension. Administration of nicotinamide riboside (NmR) has been shown to ameliorate deficiencies related to aberrant NAD(+) metabolism in both yeast and mammalian cells. However, the biological role of endogenous NmR remains unclear. Here we demonstrate that salvaging endogenous NmR is an integral part of NAD(+) metabolism. A balanced NmR salvage cycle is essential for calorie restriction-induced life span extension and stress resistance in yeast. Our results also suggest that partitioning of the pyridine nucleotide flux between the classical salvage cycle and the NmR salvage branch might be modulated by the NAD(+)-dependent Sir2 deacetylase. Furthermore, two novel deamidation steps leading to nicotinic acid mononucleotide and nicotinic acid riboside production are also uncovered that further underscore the complexity and flexibility of NAD(+) metabolism. In addition, utilization of extracellular nicotinamide mononucleotide requires prior conversion to NmR mediated by a periplasmic phosphatase Pho5. Conversion to NmR may thus represent a strategy for the transport and assimilation of large nonpermeable NAD(+) precursors. Together, our studies provide a molecular basis for how NAD(+) homeostasis factors confer metabolic flexibility.
From the Department of Microbiology, University of California, Davis, California 95616.
Shu-Ping
SP
Lu
From the Department of Microbiology, University of California, Davis, California 95616.
Michiko
M
Kato
From the Department of Microbiology, University of California, Davis, California 95616. Electronic address: slin@ucdavis.edu.
Su-Ju
SJ
Lin
D000818:Animals; D031204:Caloric Restriction; D005800:Genes, Fungal; D006655:Histone Deacetylases / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects; D008136:Longevity / Q000502:physiology; D008322:Mammals; D008954:Models, Biological; D009154:Mutation; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D011726:Pyridinium Compounds; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism; D056565:Sirtuin 2; D037761:Sirtuins / Q000378:metabolism; D013312:Stress, Physiological; D013997:Time Factors
D011726:Pyridinium Compounds; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide; D010430:Pentosyltransferases; D009699:N-Glycosyl Hydrolases; C454867:URH1 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases; C021864:nicotinate phosphoribosyltransferase