Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans
Bieganowski P, Brenner C
Key finding
NR is a distinct NAD+ precursor in humans, converted via the conserved NRK1/NRK2 kinases — a route independent of the Preiss-Handler pathway.
Summary
Seminal paper identifying nicotinamide riboside (NR) as a bona fide NAD+ precursor vitamin and defining the nicotinamide riboside kinase (NRK1/NRK2) pathway that converts it to NMN and then NAD+ independently of the classical Preiss-Handler route. Using yeast genetics, Bieganowski and Brenner screened for suppressors of a qns1 NAD+ auxotroph and recovered NR as a salvageable precursor. They cloned the NRK1 gene, then identified the human orthologs NRK1 (NMRK1) and NRK2 (NMRK2), showing both possessed kinase activity on NR. This established a third route to NAD+ in mammals, alongside the de novo tryptophan pathway and the Preiss-Handler route from nicotinic acid. The discovery directly enabled the development of NR as an oral supplement — because the NRK pathway is present in humans, dietary NR could be converted to NAD+ in tissues without requiring deamidation. Every subsequent NR clinical trial traces to this mechanistic foundation.
Access the full paper
Related research
Nature Communications · 2016
Nicotinamide riboside is uniquely and orally bioavailable in mice and humans
NR is orally bioavailable in humans and raises blood NAD+ without flushing.
Cell Reports · 2019
Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome
NR raises tissue NAD+ in aged muscle and shifts mitochondrial transcription.
Scientific Reports · 2019
Safety and metabolism of long-term administration of NIAGEN (Nicotinamide Riboside Chloride) in healthy middle-aged and older adults
NR is well tolerated at doses up to 1 g/day over 8 weeks in healthy adults.