Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid

• Published in: The Journal of biological chemistry 2017-07, Vol.292 (27), p.11147-11153
• Main Authors: McReynolds, Melanie R., Wang, Wenqing, Holleran, Lauren M., Hanna-Rose, Wendy
• Format: Article
• Language: English
• Subjects: Accelerated Communications; Animals; Caenorhabditis elegans (C. elegans); Caenorhabditis elegans - enzymology; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; metabolic tracer; metabolism; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Mutation; NAD - biosynthesis; NAD - genetics; Orotate Phosphoribosyltransferase - genetics; Orotate Phosphoribosyltransferase - metabolism; Orotidine-5'-Phosphate Decarboxylase - genetics; Orotidine-5'-Phosphate Decarboxylase - metabolism; Quinolinic Acid - metabolism; tryptophan; Tryptophan - genetics; Tryptophan - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C117.795344

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, Caenorhabditis elegans are reported to lack a de novo 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 de novo NAD+ biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact de novo 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 pnc-1, which encodes a nicotinamidase required for NAD+ salvage biosynthesis, demonstrating contribution of de novo 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.