SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters

Nicotinamide, a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrated that equilibrative nucleoside transporters 1 and 2 (ENT1 and 2, encoded by SLC29A1/2) drove cellular nicotinamide uptake and set nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibited a strong capacity to change the composition of cellular metabolites and the profile of transcripts, especially those related to nicotinamide. Then, we further found that ENT1/2 could regulate cellular respiration and senescence, which are universally acknowledged as nicotinamide biological functions, to which the NAD+ pool level and mitochondrial status influenced by ENT1/2 made important contributions. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.