Title | NRH salvage and conversion to NAD+ requires NRH kinase activity by adenosine kinase. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Yang Y, Zhang N, Zhang G, Sauve AA |
Journal | Nat Metab |
Volume | 2 |
Issue | 4 |
Pagination | 364-379 |
Date Published | 2020 Apr |
ISSN | 2522-5812 |
Keywords | Adenosine Kinase, Animals, Cells, Cultured, Mice, NAD, Niacinamide, Phosphorylation |
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. |
DOI | 10.1038/s42255-020-0194-9 |
Alternate Journal | Nat Metab |
PubMed ID | 32694608 |
PubMed Central ID | PMC7384296 |
Grant List | R01 GM106072 / GM / NIGMS NIH HHS / United States |