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Drug
Enzyme
Compound
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Target Concepts:
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Query: UMLS:C0028754 (
obesity
)
124,988
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Uridine monophosphate synthetase enables eukaryotic
de novo
NAD
+
biosynthesis from quinolinic acid. 2855 81
