Open AccessNRH salvage and conversion to NAD+ requires NRH kinase activity by adenosine kinase
Author(s) -
Yue Yang,
Ning Zhang,
Guoan Zhang,
Anthony A. Sauve
Publication year - 2020
Publication title -
nature metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.834
H-Index - 22
ISSN - 2522-5812
DOI - 10.1038/s42255-020-0194-9
Subject(s) - nad+ kinase , adenosine kinase , biochemistry , nicotinamide mononucleotide , nucleotide salvage , kinase , chemistry , enzyme , biology , nicotinamide adenine dinucleotide , nucleotide , adenosine deaminase , gene
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.