Identification of Isn1 and Sdt1 as glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid mononucleotide [corrected] 5'-nucleotidases responsible for production of nicotinamide riboside and nicotinic acid riboside

Katrina L Bogan; Charles Evans; Peter Belenky; Peng Song; Charles F Burant; Robert Kennedy; Charles Brenner

doi:10.1074/jbc.M109.056689

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Identification of Isn1 and Sdt1 as glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid mononucleotide [corrected] 5'-nucleotidases responsible for production of nicotinamide riboside and nicotinic acid riboside

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Identification of Isn1 and Sdt1 as glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid mononucleotide [corrected] 5'-nucleotidases responsible for production of nicotinamide riboside and nicotinic acid riboside

Katrina L Bogan, Charles Evans, Peter Belenky, Peng Song, Charles F Burant, Robert Kennedy and Charles Brenner

The Journal of biological chemistry, Vol.284(50), pp.34861-34869

12/11/2009

DOI: 10.1074/jbc.M109.056689

PMCID: PMC2823408

PMID: 19846558

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Abstract

Recently, we discovered that nicotinamide riboside and nicotinic acid riboside are biosynthetic precursors of NAD(+), which are utilized through two pathways consisting of distinct enzymes. In addition, we have shown that exogenously supplied nicotinamide riboside is imported into yeast cells by a dedicated transporter, and it extends replicative lifespan on high glucose medium. Here, we show that nicotinamide riboside and nicotinic acid riboside are authentic intracellular metabolites in yeast. Secreted nicotinamide riboside was detected with a biological assay, and intracellular levels of nicotinamide riboside, nicotinic acid riboside, and other NAD(+) metabolites were determined by a liquid chromatography-mass spectrometry method. A biochemical genomic screen indicated that three yeast enzymes possess nicotinamide mononucleotide 5'-nucleotidase activity in vitro. Metabolic profiling of knock-out mutants established that Isn1 and Sdt1 are responsible for production of nicotinamide riboside and nicotinic acid riboside in cells. Isn1, initially classified as an IMP-specific 5'-nucleotidase, and Sdt1, initially classified as a pyrimidine 5'-nucleotidase, are additionally responsible for dephosphorylation of pyridine mononucleotides. Sdt1 overexpression is growth-inhibitory to cells in a manner that depends on its active site and correlates with reduced cellular NAD(+). Expression of Isn1 protein is positively regulated by the availability of nicotinic acid and glucose. These results reveal unanticipated and highly regulated steps in NAD(+) metabolism.

Niacinamide - analogs & derivatives

5'-Nucleotidase - genetics

NAD - analogs & derivatives

Niacinamide - metabolism

Saccharomyces cerevisiae - genetics

Nicotinamide Mononucleotide - metabolism

Vitamins - metabolism

Saccharomyces cerevisiae Proteins - genetics

Gene Knockout Techniques

Niacin - metabolism

Saccharomyces cerevisiae - metabolism

Ribonucleosides - metabolism

Saccharomyces cerevisiae Proteins - metabolism

Glucose - metabolism

5'-Nucleotidase - metabolism

NAD - metabolism

Details

Title: Subtitle: Identification of Isn1 and Sdt1 as glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid mononucleotide [corrected] 5'-nucleotidases responsible for production of nicotinamide riboside and nicotinic acid riboside
Creators: Katrina L Bogan - Biochemistry Graduate Program, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA
Charles Evans
Peter Belenky
Peng Song
Charles F Burant
Robert Kennedy
Charles Brenner
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.284(50), pp.34861-34869
DOI: 10.1074/jbc.M109.056689
PMID: 19846558
PMCID: PMC2823408
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: R37-DK046960 / NIDDK NIH HHS R37 DK046960 / NIDDK NIH HHS T32 DK007245 / NIDDK NIH HHS R01-DK079084 / NIDDK NIH HHS T32-DK07245 / NIDDK NIH HHS R01 DK079084 / NIDDK NIH HHS
Language: English
Date published: 12/11/2009
Academic Unit: Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9983788430502771

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