Nicotinamide Phosphoribosyltransferase/Visfatin Does Not Catalyze Nicotinamide Mononucleotide Formation in Blood Plasma
Open accessAbstract
Nicotinamide (Nam) phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in mammalian NAD synthesis, catalyzing nicotinamide mononucleotide (NMN) formation from Nam and 5-phosphoribosyl 1-pyrophosphate (PRPP). NAMPT has also been described as an adipocytokine visfatin with a variety of actions, although physiological significance of this protein remains unclear. It has been proposed that possible actions of visfatin are mediated through the extracellular formation of NMN. However, we did not detect NMN in mouse blood plasma, even with a highly specific and sensitive liquid chromatography/tandem mass spectrometry. Furthermore, there is no or little ATP, the activator of NAMPT, in extracellular spaces. We thus questioned whether visfatin catalyzes the in situ formation of NMN under such extracellular milieus. To address this question, we here determined K(m) values for the substrates Nam and PRPP in the NAMPT reaction without or with ATP using a recombinant human enzyme and found that 1 mM ATP dramatically decreases K(m) values for the substrates, in particular PRPP to its intracellular concentration. Consistent with the kinetic data, only when ATP is present at millimolar levels, NAMPT efficiently catalyzed the NMN formation at the intracellular concentrations of the substrates. Much lower concentrations of Nam and almost the absence of PRPP and ATP in the blood plasma suggest that NAMPT should not efficiently catalyze its reaction under the extracellular milieu. Indeed, NAMPT did not form NMN in the blood plasma. From these kinetic analyses of the enzyme and quantitative determination of its substrates, activator, and product, we conclude that visfatin does not participate in NMN formation under the extracellular milieus. Together with the absence of NMN in the blood plasma, our conclusion does not support the concept of "NAMPT-mediated systemic NAD biosynthesis." Our study would advance current understanding of visfatin physiology.
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Our study and others have failed to detect comparable levels of circulating NMN to the reported ~50 μM in plasma.
“Whereas NMN concentration has been reported to reach around 50 μM in plasma14, our study and others13 have failed to detect comparable levels of circulating NMN.”
From NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells (2016) · cites this paper as [13]
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- Authors
- Hara, N., Yamada, K., Shibata, T., Osago, H., & Tsuchiya, M.
- Affiliations
- Shimane University (JP)
- Corresponding author
- Hara, Nobumasa
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-08-03
- Volume
- 6
- Issue
- 8
- Pages
- e22781
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3149623
- OpenAlex
- W2131005104
- Cited by
- 116
- References
- 37
- Citations by year
- 2025: 7 · 2024: 7 · 2023: 7 · 2022: 12 · 2021: 4 · 2020: 9 · 2019: 6 · 2018: 8 · 2017: 14 · 2016: 4 · 2015: 9 · 2014: 8 · 2013: 10 · 2012: 11
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science (21580139)
- 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
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- visfatin, nicotinamide mononucleotide, NAD biosynthesis, blood plasma, enzyme kinetics, substrate Km, ATP stimulation, 5-phosphoribosyl-1-pyrophosphate, nicotinamide
- MeSH terms
- Animals, Humans, Mice, Inbred C57BL, Niacinamide, Nicotinamide Mononucleotide, Organophosphorus Compounds, Plasma, Mice, Nicotinamide Phosphoribosyltransferase
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