Abstract
Nicotinamide mononucleotide (NMN) is a widely investigated metabolic precursor to the prominent enzyme cofactor NAD+, where it is assumed that delivery of this compound results in its direct incorporation into NAD+via the canonical salvage/recycling pathway. Surprisingly, treatment with this salvage pathway intermediate leads to increases in nicotinic acid mononucleotide (NaMN) and nicotinic acid adenine dinucleotide, two members of the Preiss-Handler/de novo pathways. In mammals, these pathways are not known to intersect prior to the production of NAD+. Here, we show that the cell surface enzyme CD38 can mediate a base-exchange reaction on NMN, whereby the nicotinamide ring is exchanged with a free nicotinic acid to yield the Preiss-Handler/de novo pathway intermediate NaMN, with in vivo small molecule inhibition of CD38 abolishing the NMN-induced increase in NaMN and nicotinic acid adenine dinucleotide. Together, these data demonstrate a new mechanism by which the salvage pathway and Preiss-Handler/de novo pathways can exchange intermediates in mammalian NAD+ biosynthesis.
Keywords:
CD38; Preiss–Handler pathway; base exchange; metabolomics; nicotinamide adenine dinucleotide (NAD+); nicotinamide adenine dinucleotide (NAD+) biosynthesis; nicotinamide mononucleotide (NMN); nicotinic acid mononucleotide (NaMN); salvage pathway; stable isotopes; transglycosidase; transglycosylase; transglycosylation.