NRH salvage and conversion to NAD+ requires NRH kinase activity by adenosine kinase

Nat Metab. 2020 Apr;2(4):364-379. doi: 10.1038/s42255-020-0194-9. Epub 2020 Apr 21.

Abstract

Dihydronicotinamide riboside (NRH) has been suggested to act as a precursor for the synthesis of NAD+, but the biochemical pathway converting it has been unknown. Here, we show that NRH can be converted into NAD+ via a salvage pathway in which adenosine kinase (ADK, also known as AK) acts as an NRH kinase. Using isotope-labelling approaches, we demonstrate that NRH is fully incorporated into NAD+, with NMNH acting as an intermediate. We further show that AK is enriched in fractions from cell lysates with NRH kinase activity, and that AK can convert NRH into NAD+. In cultured cells and mouse liver, pharmacological or genetic inhibition of AK blocks formation of reduced nicotinamide mononucleotide (NMNH) and inhibits NRH-stimulated NAD+ biosynthesis. Finally, we confirm the presence of endogenous NRH in the liver with metabolomics. Our findings establish NRH as a natural precursor of NAD+ and reveal a new route for NAD+ biosynthesis via an NRH salvage pathway involving AK.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Kinase / metabolism*
  • Animals
  • Cells, Cultured
  • Mice
  • NAD / metabolism*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Phosphorylation

Substances

  • dihydronicotinamide
  • NAD
  • Niacinamide
  • Adenosine Kinase