科研之友
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摘要
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.
- 出版日期2017-7-7
