CD38 mediates nicotinamide mononucleotide base exchange to yield nicotinic acid mononucleotide

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.