CD38 mediates nicotinamide mononucleotide (NMN) base exchange to yield nicotinic acid mononucleotide (NaMN)

Nicotinamide mononucleotide (NMN) is a widely investigated metabolic precursor to the prominent redox cofactor nicotinamide adenine dinucleotide (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 (NaAD), 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 NaAD. 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.