RRC ID 51403
Author McReynolds MR, Wang W, Holleran LM, Hanna-Rose W.
Title Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid.
Journal J Biol Chem
Abstract 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.
Volume 292(27)
Pages 11147-11153
Published 2017-7-7
DOI 10.1074/jbc.C117.795344
PII C117.795344
PMID 28559281
PMC PMC5500784
MeSH Animals Caenorhabditis elegans* / enzymology Caenorhabditis elegans* / genetics Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / 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 / genetics Tryptophan / metabolism
IF 4.238
Times Cited 5
Resource
C.elegans tm4924 tm6379