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


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.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC7384296 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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NRH salvage and conversion to NAD<sup>+</sup> requires NRH kinase activity by adenosine kinase.

Yang Yue Y   Zhang Ning N   Zhang Guoan G   Sauve Anthony A AA  

Nature metabolism 20200421 4


Dihydronicotinamide riboside (NRH) has been suggested to act as a precursor for the synthesis of NAD<sup>+</sup>, but the biochemical pathway converting it has been unknown. Here, we show that NRH can be converted into NAD<sup>+</sup> 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<sup>+</sup>, with NMNH acting as an intermediate. We further show that AK is en  ...[more]

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