Cross-talk in NAD+ metabolism: insights from Saccharomyces cerevisiae

Abstract

NAD⁺ (nicotinamide adenine dinucleotide) is an essential metabolite involved in a myriad of cellular processes. The NAD⁺ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human with some species-specific differences. Studying the regulation of NAD⁺ metabolism has been difficult due to the dynamic flexibility of NAD⁺ intermediates, the redundancy of biosynthesis pathways, and the complex interconnections among them. The budding yeast Saccharomyces cerevisiae provides an efficient genetic model for the isolation and study of factors that regulate specific NAD⁺ biosynthesis pathways. A recent study has uncovered a putative cross-regulation between the de novo NAD⁺ biosynthesis and copper homeostasis mediated by a copper-sensing transcription factor Mac1. Mac1 appears to work with the Hst1-Sum1-Rfm1 complex to repress the expression of de novo NAD⁺ biosynthesis genes. Here, we extend the discussions to include additional nutrient- and stress-sensing pathways that have been associated with the regulation of NAD⁺ homeostasis. NAD⁺ metabolism is an emerging therapeutic target for several human diseases. NAD⁺ preservation also helps ameliorate age-associated metabolic disorders. Recent findings in yeast contribute to the understanding of the molecular basis underlying the cross-regulation of NAD⁺ metabolism and other signaling pathways.

Keywords: Gene silencing; NAD+ metabolism; Nutrient signaling; Sir2 family; Stress signaling; Transcription.

Fig. 1. NAD⁺ biosynthesis pathways in budding yeast Saccharomyces cerevisiae.

NAD⁺ can be synthesized de novo or salvaged from intermediates and small precursors such as NA, NAM and NR. Yeast cells also release and re-uptake these precursors. The de novo NAD⁺ synthesis (left panel) is mediated by Bna2,7,4,5,1,6 proteins leading to the production of NaMN. The NA/NAM salvage pathway (center panel) also produces NaMN, which is then converted to NaAD and NAD⁺ by Nma1/2 and Qns1, respectively. NR salvage (right panel) connects to the NA/NAM salvage pathway by Urh1, Pnp1 and Meu1. NR turns into NMN by Nrk1, which is then converted to NAD⁺ by Nma1, Nma2 and Pof1. For clarity, this model centers on NA/NAM salvage (highlighted with bold black arrows) because standard growth media contain abundant NA. Arrows with dashed lines indicate the mechanisms of these pathways remain largely unclear. NA, nicotinic acid. NAM, nicotinamide. NR, nicotinamide riboside. QA, quinolinic acid. L-TRP, L-tryptophan. NFK, N-formylkynurenine. L-KYN, L-kynurenine. 3-HK, 3-hydroxykynurenine. 3-HA, 3-hydroxyanthranilic acid. NaMN, nicotinic acid mononucleotide. NaAD, deamido-NAD⁺. NMN, nicotinamide mononucleotide. Abbreviations of protein names are shown in parentheses. Bna2, tryptophan 2,3-dioxygenase. Bna7, kynurenine formamidase. Bna4, kynurenine 3-monooxygenase. Bna5, kynureninase. Bna1, 3-hydroxyanthranilate 3,4-dioxygenase. Bna6, quinolinic acid phosphoribosyl transferase. Nma1/2, NaMN/NMN adenylyltransferase. Qns1, glutamine-dependent NAD⁺ synthetase. Npt1, nicotinic acid phosphoribosyl transferase. Pnc1, nicotinamide deamidase. Sir2 family, NAD^+- dependent protein deacetylases. Urh1, Pnp1 and Meu1, nucleosidases. Nrk1, NR kinase. Isn1 and Sdt1, nucelotidases. Pho8 and Pho5, phosphatases. Pof1, NMN adenylyltransferase. Tna1, NA and QA transporter. Nrt1, NR transporter.

Fig. 2. A simplified model depicting the interactions of NAD⁺ metabolism and cellular signaling pathways.

Under NA abundant conditions (standard growth media), NA/NAM salvage is the preferred NAD⁺ biosynthesis route, and BNA genes are repressed by the NAD⁺-dependent histone deacetylase Hst1. NAM contributes to NAD⁺ synthesis via NA/NAM salvage. NAM also de-represses BNA gene expression and de novo QA synthesis by inhibiting Hst1 activity. The copper-sensing transcription factor Mac1 appears to work in concert with the Hst1-containing repressor complex to repress BNA genes. Several nutrient sensing pathways including glucose sensing, amino acid sensing and phosphate (Pi) sensing pathways have also been connected to NAD⁺ metabolism. Dashed lines indicate the mechanisms of these pathways remain largely unclear.