Structural Insights Into Nicotinamide Riboside Kinase Reveal How Cells Make NAD+: Preclinical Findings

Synopsis

The nicotinamide riboside kinase (Nrk) pathway, active in eukaryotic cells, plays a vital role in converting nicotinamide riboside into nicotinamide adenine dinucleotide (NAD⁺), an essential molecule for cellular metabolism and repair. This pathway is activated in response to nerve damage and is also known to extend the replicative lifespan of yeast cells. By analyzing the crystal structures of human Nrk1 bound to its substrates and products, researchers found that Nrk1 shares structural similarities with Rossmann fold metabolite kinases. These detailed structures helped identify key active site residues that are crucial for the enzymatic activity of both human Nrk1 and Nrk2 in living cells. The structural studies also revealed that Nrk enzymes can distinguish between nicotinamide riboside and other nucleosides with remarkable specificity—over 500-fold—although no unique structural feature was found to explain recognition of nicotinamide’s carboxamide group. Surprisingly, the enzymes were also found to use nicotinic acid riboside as a substrate, revealing a previously unknown route for NAD⁺ biosynthesis. This alternative pathway involves Nrk, NAD⁺ synthetase, and additional enzymes like Urh1, Pnp1, and those of the Preiss-Handler salvage pathway. Overall, the discovery of Nrk1’s structure and substrate flexibility expands our understanding of how cells generate NAD⁺ and adapt to metabolic and stress-related challenges.

Journal

PLoS Biology