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The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells
Open accessAbstract
Recent studies have revealed new roles for NAD and its derivatives in transcriptional regulation. The evolutionarily conserved Sir2 protein family requires NAD for its deacetylase activity and regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Despite its absolute requirement for NAD, the regulation of Sir2 function by NAD biosynthesis pathways is poorly understood in mammals. In this study, we determined the kinetics of the NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (Nmnat), and we examined its effects on the transcriptional regulatory function of the mouse Sir2 ortholog, Sir2alpha, in mouse fibroblasts. We found that Nampt was the rate-limiting component in this mammalian NAD biosynthesis pathway. Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2alpha recruited onto a reporter gene in mouse fibroblasts. Gene expression profiling with oligonucleotide microarrays also demonstrated a significant correlation between the expression profiles of Nampt- and Sir2alpha-overexpressing cells. These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2alpha and thereby plays an important role in controlling various biological events in mammals.
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“NMN is an intermediate in the salvage pathway and can be converted to NAD+, bypassing a catalysis of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in this pathway (10).”
From Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD + synthesis via enterohepatic circulation (2025) · cites this paper as [10]
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“NMN is a substrate for nicotinamide mononucleotide adenylyltransferase (NMNAT), which is an enzyme that converts NMN and adenosine triphosphate to NAD+ and inorganic pyrophosphate (10).”
From Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD + synthesis via enterohepatic circulation (2025) · cites this paper as [10]
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Metadata
- Authors
- Revollo, J. R., Grimm, A. A., & Imai, S.-I.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Imai, Shin-ichiro
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 279
- Issue
- 49
- Pages
- 50754-50763
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2108536847
- Cited by
- 1,010
- References
- 61
- Citations by year
- 2026: 31 · 2025: 34 · 2024: 54 · 2023: 43 · 2022: 52 · 2021: 49 · 2020: 57 · 2019: 51 · 2018: 56 · 2017: 62 · 2016: 48 · 2015: 51 · 2014: 41 · 2013: 58 · 2012: 55
- FWCI
- 9.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- Leukemia and Lymphoma Society
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- NAD biosynthesis, visfatin, nicotinamide mononucleotide adenylyltransferase, rate-limiting enzyme, mouse fibroblasts, gene expression profiling, aging
- MeSH terms
- Animals, Cell Differentiation, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Fibroblasts, Fungal Proteins, Kinetics, Luciferases, NAD, Nicotinamide-Nucleotide Adenylyltransferase, Pentosyltransferases, Phylogeny, Recombinant Proteins, Saccharomyces cerevisiae, Transcription, Genetic, Blotting, Western, Gene Library, Cytokines, Genes, Reporter, DNA, Complementary, Reverse Transcriptase Polymerase Chain Reaction, Catalytic Domain, Oligonucleotide Array Sequence Analysis, Sirtuins, NIH 3T3 Cells, Mice, Nicotinamide Phosphoribosyltransferase, Sirtuin 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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