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

TitleNRH salvage and conversion to NAD+ requires NRH kinase activity by adenosine kinase.
Publication TypeJournal Article
Year of Publication2020
AuthorsYang Y, Zhang N, Zhang G, Sauve AA
JournalNat Metab
Volume2
Issue4
Pagination364-379
Date Published2020 Apr
ISSN2522-5812
KeywordsAdenosine 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.

DOI10.1038/s42255-020-0194-9
Alternate JournalNat Metab
PubMed ID32694608
PubMed Central IDPMC7384296
Grant ListR01 GM106072 / GM / NIGMS NIH HHS / United States