Blocking PNP Increases Nicotinamide Riboside Effectiveness for NAD+: Preclinical Findings

Synopsis

Nicotinamide riboside (NR), a vitamin B3 derivative and precursor to nicotinamide adenine dinucleotide (NAD+), helps boost cellular energy and repair mechanisms. While NR supplementation can raise NAD+ levels and improve metabolic and age-related conditions, its efficacy varies, partly because its metabolism inside cells is not fully understood. This study identified purine nucleoside phosphorylase (PNP) as a major enzyme that breaks down NR once it enters cells through equilibrative nucleoside transporters (ENTs). PNP converts NR into nicotinamide (Nam), which limits how much NAD+ the body can synthesize from NR. Blocking PNP activity with the inhibitor Immucillin H prevented this breakdown, allowing higher NR retention and more efficient NAD+ production. In mice, combining PNP inhibition with NR supplementation maintained elevated NR levels in the blood, liver, and kidneys, significantly enhancing the formation of nicotinamide mononucleotide (NMN) and NAD+—especially in kidney tissue. Overall, the study identifies PNP as a key regulator of NR metabolism and suggests that inhibiting PNP could greatly boost the effectiveness of NR supplements, improving NAD+ restoration and metabolic health in humans.

Journal

Journal of Biological Chemistry