Secretion of Quinolinic Acid, an Intermediate in the Kynurenine Pathway, for Utilization in NAD ⁺ Biosynthesis in the Yeast Saccharomyces cerevisiae

Abstract

NAD؉ is synthesized from tryptophan either via the kynurenine (de novo) pathway or via the salvage pathway by reutilizing intermediates such as nicotinic acid or nicotinamide ribose. Quinolinic acid is an intermediate in the kynurenine pathway. We have discovered that the budding yeast Saccharomyces cerevisiae secretes quinolinic acid into the medium and also utilizes extracellular quinolinic acid as a novel NAD ؉ precursor. We provide evidence that extracellular quinolinic acid enters the cell via Tna1, a high-affinity nicotinic acid permease, and thereby helps to increase the intracellular concentration of NAD ؉ . Transcription of genes involved in the kynurenine pathway and Tna1 was increased, responding to a low intracellular NAD ؉ concentration, in cells bearing mutations of these genes; this transcriptional induction was suppressed by supplementation with quinolinic acid or nicotinic acid. Our data thus shed new light on the significance of quinolinic acid, which had previously been recognized only as an intermediate in the kynurenine pathway.

Reduced Ssy1-Ptr3-Ssy5 (SPS) Signaling Extends Replicative Life Span by Enhancing NAD+ Homeostasis in Saccharomyces cerevisiae

“…To identify the source of elevated NR in ssy5⌬ cells (Fig. 2F), we examined the gene expression of pathways known to produce and salvage NAD ϩ and NR (8,10,(45)(46)(47). Expression levels of the genes in NAD ϩ synthetic pathways generally remained similar between WT and ssy5⌬ cells as we expected (Fig.…”

Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae

“…Ohashi et al . showed that quinolinic acid (QA) is also produced and excreted like NR (16). Thus, it is possible that pyridine nucleotides and their metabolites are involved in a variety of cellular processes and balancing their concentrations would be critical for the regulation of these processes.…”

“…NA can be generated from Nam mediated by the Nam deamidase Pnc1 ( p yrazineamidase and n i c otinamidase) as part of the salvaging reactions. Both NA and QA can also be acquired from the environment by the NA transporter Tna1 ( t ransporter of n icotinic a cid) (16,17). De novo synthesis and NA/Nam salvaging pathways converge at NaMN, which is converted to deamido-NAD + (NaAD) by transferring the AMP moiety of ATP by Nma1 and Nma2 (NMNATs).…”

Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD+ homeostasis and contributes to longevity

“…As part of NA/NAM salvage, another phosphoribosyltransferase, Npt1, converts NA into NaMN (Preiss et al, 1958; Preiss et al, 1958). NA is mainly salvaged from Nam by Pnc1 deamidase, but the NA transporter, Tna1, also imports both NA and QA (Llorente et al, 2000; Ohashi et al, 2013). Next, NaMN a denylyltransferases, (NaMNATs), Nma1 and Nma2, convert NaMN into nicotinic acid adenine dinucleotide (NaAD or deamido-NAD + ) by transfer of the AMP moiety from ATP.…”

“…In yeast, we recently showed that NMN is constantly converted into NR, which is more mobile and readily excreted, re-assimilated or sent to storage (Kato et al, 2014). The NAD + intermediate, QA, was also shown to be produced and excreted like NR (Ohashi et al, 2013). Additionally, Nam is a product and inhibitor of NAD + -dependent deacetylase, Sir2, thus Nam clearance is critical for Sir2 activity and life span (Gallo et al, 2004) (see 8.1 Sir2 and NAD + metabolism).…”