CD38 Converts NMN to NaMN Through Base Exchange: Preclinical Findings

Synopsis

Nicotinamide mononucleotide (NMN) is generally assumed to boost NAD+ by feeding directly into the canonical salvage pathway. However, this study shows that NMN treatment unexpectedly increases levels of nicotinic acid mononucleotide (NaMN) and nicotinic acid adenine dinucleotide, metabolites from the Preiss–Handler/de novo pathways, which traditionally do not intersect with the salvage pathway before forming NAD+. The cell-surface enzyme CD38 was identified as the mediator of this conversion: CD38 performs a base-exchange reaction, swapping the nicotinamide moiety of NMN with nicotinic acid, generating NaMN. Interestingly, the same base-exchange activity was not observed with nicotinamide riboside (NR), confirming that NR does not undergo this conversion. Pharmacological inhibition of CD38 in vivo blocked these NMN-induced increases in NaMN and downstream metabolites. These findings reveal a previously unknown point of metabolic cross-talk between NAD+ biosynthetic pathways, showing that NMN can be rerouted into the Preiss–Handler/de novo pathways via CD38.

Journal

Journal of Biological Chemistry