Nicotinamide riboside kinase structures reveal new pathways to NAD

Wolfram Tempel; Wael M Rabeh; Katrina L Bogan; Peter Belenky; Marzena Wojcik; Heather F Seidle; Lyudmila Nedyalkova; Tianle Yang; Anthony A Sauve; Hee-Won Park; Charles Brenner

doi:10.1371/journal.pbio.0050263

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Nicotinamide riboside kinase structures reveal new pathways to NAD

Journal article

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Peer reviewed

Nicotinamide riboside kinase structures reveal new pathways to NAD

Wolfram Tempel, Wael M Rabeh, Katrina L Bogan, Peter Belenky, Marzena Wojcik, Heather F Seidle, Lyudmila Nedyalkova, Tianle Yang, Anthony A Sauve, Hee-Won Park, …

PLoS biology, Vol.5(10), pp.2220-2230

10/02/2007

DOI: 10.1371/journal.pbio.0050263

PMCID: PMC1994991

PMID: 17914902

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Abstract

The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+) by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+.

Phosphorylation

Phosphotransferases (Alcohol Group Acceptor) - chemistry

Humans

Molecular Sequence Data

Protein Conformation

Binding Sites

NAD - metabolism

Phosphotransferases (Alcohol Group Acceptor) - metabolism

Details

Title: Subtitle: Nicotinamide riboside kinase structures reveal new pathways to NAD
Creators: Wolfram Tempel - Structural Genomics Consortium and Department of Pharmacology, University of Toronto, Toronto, Canada
Wael M Rabeh
Katrina L Bogan
Peter Belenky
Marzena Wojcik
Heather F Seidle
Lyudmila Nedyalkova
Tianle Yang
Anthony A Sauve
Hee-Won Park
Charles Brenner
Resource Type: Journal article
Publication Details: PLoS biology, Vol.5(10), pp.2220-2230
DOI: 10.1371/journal.pbio.0050263
PMID: 17914902
PMCID: PMC1994991
NLM abbreviation: PLoS Biol
ISSN: 1544-9173
eISSN: 1545-7885
Publisher: United States
Grant note: DK073466 / NIDDK NIH HHS Y1-CO-1020 / NCI NIH HHS Y1-GM-1104 / NIGMS NIH HHS R01 DK073466 / NIDDK NIH HHS
Language: English
Date published: 10/02/2007
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788430802771

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