Uridine monophosphate synthetase enables eukaryotic NAD biosynthesis from quinolinic acid.

NAD biosynthesis is an attractive and promising therapeutic target for influencing health span and obesity-related phenotypes as well as tumor growth. Full and effective use of this target for therapeutic benefit requires a complete understanding of NAD biosynthetic pathways. Here, we report a previously unrecognized role for a conserved phosphoribosyltransferase in NAD biosynthesis. Because a required quinolinic acid phosphoribosyltransferase (QPRTase) is not encoded in its genome, are reported to lack a NAD biosynthetic pathway. However, all the genes of the kynurenine pathway required for quinolinic acid (QA) production from tryptophan are present. Thus, we investigated the presence of NAD biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact biosynthesis pathway for NAD from tryptophan via QA, highlighting the functional conservation of this important biosynthetic activity. Supplementation with kynurenine pathway intermediates also boosted NAD levels and partially reversed NAD-dependent phenotypes caused by mutation of , which encodes a nicotinamidase required for NAD salvage biosynthesis, demonstrating contribution of synthesis to NAD homeostasis. By investigating candidate phosphoribosyltransferase genes in the genome, we determined that the conserved uridine monophosphate phosphoribosyltransferase (UMPS), which acts in pyrimidine biosynthesis, is required for NAD biosynthesis in place of the missing QPRTase. We suggest that similar underground metabolic activity of UMPS may function in other organisms. This mechanism for NAD biosynthesis creates novel possibilities for manipulating NAD biosynthetic pathways, which is key for the future of therapeutics.