The Experts below are selected from a list of 1242 Experts worldwide ranked by ideXlab platform
Charles Brenner - One of the best experts on this subject based on the ideXlab platform.
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Nicotinamide Riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder
Scientific reports, 2020Co-Authors: Maria Gerasimenko, Stanislav M. Cherepanov, Kazumi Furuhara, Olga Lopatina, Alla B. Salmina, Anna A. Shabalova, Chiharu Tsuji, Shigeru Yokoyama, Katsuhiko Ishihara, Charles BrennerAbstract:Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of Nicotinamide Riboside, a recently discovered vitamin precursor of Nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide Riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with Nicotinamide Riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.
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Nicotinamide Riboside a form of vitamin b3 protects against excitotoxicity induced axonal degeneration
The FASEB Journal, 2017Co-Authors: Pauline Vaur, Charles Brenner, Mark S. Schmidt, Bernard Brugg, Mathias Mericskay, Denis Vivien, Cyrille Orset, Etienne Jacotot, Eric DuplusAbstract:NAD+ depletion is a common phenomenon in neurodegenerative pathologies. Excitotoxicity occurs in multiple neurologic disorders and NAD+ was shown to prevent neuronal degeneration in this process through mechanisms that remained to be determined. The activity of Nicotinamide Riboside (NR) in neuroprotective models and the recent description of extracellular conversion of NAD+ to NR prompted us to probe the effects of NAD+ and NR in protection against excitotoxicity. Here, we show that intracortical administration of NR but not NAD+ reduces brain damage induced by NMDA injection. Using cortical neurons, we found that provision of extracellular NR delays NMDA-induced axonal degeneration (AxD) much more strongly than extracellular NAD+ Moreover, the stronger effect of NR compared to NAD+ depends of axonal stress since in AxD induced by pharmacological inhibition of Nicotinamide salvage, both NAD+ and NR prevent neuronal death and AxD in a manner that depends on internalization of NR. Taken together, our findings demonstrate that NR is a better neuroprotective agent than NAD+ in excitotoxicity-induced AxD and that axonal protection involves defending intracellular NAD+ homeostasis.-Vaur, P., Brugg, B., Mericskay, M., Li, Z., Schmidt, M. S., Vivien, D., Orset, C., Jacotot, E., Brenner, C., Duplus, E. Nicotinamide Riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration.
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Nicotinamide Riboside, a form of vitamin B3, protects against excitotoxicity‐induced axonal degeneration
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2017Co-Authors: Pauline Vaur, Charles Brenner, Mark S. Schmidt, Bernard Brugg, Mathias Mericskay, Denis Vivien, Cyrille Orset, Etienne Jacotot, Eric DuplusAbstract:NAD+ depletion is a common phenomenon in neurodegenerative pathologies. Excitotoxicity occurs in multiple neurologic disorders and NAD+ was shown to prevent neuronal degeneration in this process through mechanisms that remained to be determined. The activity of Nicotinamide Riboside (NR) in neuroprotective models and the recent description of extracellular conversion of NAD+ to NR prompted us to probe the effects of NAD+ and NR in protection against excitotoxicity. Here, we show that intracortical administration of NR but not NAD+ reduces brain damage induced by NMDA injection. Using cortical neurons, we found that provision of extracellular NR delays NMDA-induced axonal degeneration (AxD) much more strongly than extracellular NAD+ Moreover, the stronger effect of NR compared to NAD+ depends of axonal stress since in AxD induced by pharmacological inhibition of Nicotinamide salvage, both NAD+ and NR prevent neuronal death and AxD in a manner that depends on internalization of NR. Taken together, our findings demonstrate that NR is a better neuroprotective agent than NAD+ in excitotoxicity-induced AxD and that axonal protection involves defending intracellular NAD+ homeostasis.-Vaur, P., Brugg, B., Mericskay, M., Li, Z., Schmidt, M. S., Vivien, D., Orset, C., Jacotot, E., Brenner, C., Duplus, E. Nicotinamide Riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration.
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Nicotinamide Riboside is uniquely and orally bioavailable in mice and humans
Nature communications, 2016Co-Authors: Samuel A.j. Trammell, Marie E. Migaud, Philip Redpath, Mark S. Schmidt, Benjamin J. Weidemann, Frank Jaksch, Ryan Dellinger, E. Dale Abel, Charles BrennerAbstract:Nicotinamide Riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD+ metabolism in humans. We report that human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid and Nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD+, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD+ repletion. NAD+ is an important coenzyme that mediates cellular metabolism and defends against stresses due to age and overnutrition. Here the authors demonstrate unique bioavailability of the NAD+ precursor vitamin Nicotinamide Riboside (NR) in mice and humans, and show that NR safely elevates human NAD+.
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Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice
Scientific reports, 2016Co-Authors: Samuel A.j. Trammell, Benjamin J. Weidemann, Ankita Chadda, Matthew S. Yorek, Amey Holmes, Lawrence J. Coppey, Alexander Obrosov, Randy H. Kardon, Charles BrennerAbstract:Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with Nicotinamide Riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.
Anthony A. Sauve - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of β‐Nicotinamide Riboside Using an Efficient Two‐Step Methodology
Current protocols in nucleic acid chemistry, 2017Co-Authors: Ning Zhang, Anthony A. SauveAbstract:A two-step chemical method for the synthesis of β-Nicotinamide Riboside (NR) is described. NR has achieved wide use as an NAD+ precursor (vitamin B3) and can significantly increase central metabolite NAD+ concentrations in mammalian cells. β-NR can be prepared with an efficient two-step procedure. The synthesis is initiated via coupling of commercially available 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose with ethyl nicotinate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). 1 H NMR showed that the product was formed with complete stereoselectivity to produce only the β-isomer in high yield (>90% versus starting sugar). The clean stereochemical result suggests that the coupling proceeds via a cationic cis-1,2-acyloxonium-sugar intermediate, which controls addition by nucleophiles to generate predominantly β-stereochemistry. The subsequent deprotection of esters in methanolic ammonia generates the desired product in 85% overall yield versus sugar. © 2017 by John Wiley & Sons, Inc.
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synthesis of β Nicotinamide Riboside using an efficient two step methodology
Current protocols in human genetics, 2017Co-Authors: Ning Zhang, Anthony A. SauveAbstract:A two-step chemical method for the synthesis of β-Nicotinamide Riboside (NR) is described. NR has achieved wide use as an NAD+ precursor (vitamin B3) and can significantly increase central metabolite NAD+ concentrations in mammalian cells. β-NR can be prepared with an efficient two-step procedure. The synthesis is initiated via coupling of commercially available 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose with ethyl nicotinate in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf). 1 H NMR showed that the product was formed with complete stereoselectivity to produce only the β-isomer in high yield (>90% versus starting sugar). The clean stereochemical result suggests that the coupling proceeds via a cationic cis-1,2-acyloxonium-sugar intermediate, which controls addition by nucleophiles to generate predominantly β-stereochemistry. The subsequent deprotection of esters in methanolic ammonia generates the desired product in 85% overall yield versus sugar. © 2017 by John Wiley & Sons, Inc.
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Activation of SIRT3 by the NAD+ Precursor Nicotinamide Riboside Protects from Noise-Induced Hearing Loss
Cell metabolism, 2014Co-Authors: Kevin D. Brown, Anthony A. Sauve, Sadia Maqsood, Jing Yi Huang, Yong Pan, William T. Harkcom, Eric Verdin, Samie R. JaffreyAbstract:Intense noise exposure causes hearing loss by inducing degeneration of spiral ganglia neurites that innervate cochlear hair cells. Nicotinamide adenine dinucleotide (NAD(+)) exhibits axon-protective effects in cultured neurons; however, its ability to block degeneration in vivo has been difficult to establish due to its poor cell permeability and serum instability. Here, we describe a strategy to increase cochlear NAD(+) levels in mice by administering Nicotinamide Riboside (NR), a recently described NAD(+) precursor. We find that administration of NR, even after noise exposure, prevents noise-induced hearing loss (NIHL) and spiral ganglia neurite degeneration. These effects are mediated by the NAD(+)-dependent mitochondrial sirtuin, SIRT3, since SIRT3-overexpressing mice are resistant to NIHL and SIRT3 deletion abrogates the protective effects of NR and expression of NAD(+) biosynthetic enzymes. These findings reveal that administration of NR activates a NAD(+)-SIRT3 pathway that reduces neurite degeneration caused by noise exposure.
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Nicotinamide Riboside a trace nutrient in foods is a vitamin b3 with effects on energy metabolism and neuroprotection
Current Opinion in Clinical Nutrition and Metabolic Care, 2013Co-Authors: Yuling Chi, Anthony A. SauveAbstract:Purpose of reviewThis review focuses upon the biology and metabolism of a trace component in foods called Nicotinamide Riboside. Nicotinamide Riboside is a precursor of Nicotinamide adenine dinucleotide (NAD+), and is a source of Vitamin B3. Evidence indicates that Nicotinamide Riboside has unique p
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Nicotinamide Riboside, a trace nutrient in foods, is a vitamin B3 with effects on energy metabolism and neuroprotection.
Current opinion in clinical nutrition and metabolic care, 2013Co-Authors: Yuling Chi, Anthony A. SauveAbstract:This review focuses upon the biology and metabolism of a trace component in foods called Nicotinamide Riboside. Nicotinamide Riboside is a precursor of Nicotinamide adenine dinucleotide (NAD), and is a source of Vitamin B3. Evidence indicates that Nicotinamide Riboside has unique properties as a Vitamin B3. We review knowledge of the metabolism of this substance, as well as recent work suggesting novel health benefits that might be associated with Nicotinamide Riboside taken in larger quantities than is found naturally in foods. Recent work investigating the effects of Nicotinamide Riboside in yeast and mammals established that it is metabolized by at least two types of metabolic pathways. The first of these is degradative and produces Nicotinamide. The second pathway involves kinases called Nicotinamide Riboside kinases (Nrk1 and Nrk2, in humans). The likely involvement of the kinase pathway is implicated in the unique effects of Nicotinamide Riboside in raising tissue NAD concentrations in rodents and for potent effects in eliciting insulin sensitivity, mitochondrial biogenesis, and enhancement of sirtuin functions. Additional studies with Nicotinamide Riboside in models of Alzheimer's disease indicate bioavailability to brain and protective effects, likely by stimulation of brain NAD synthesis. Initial studies have clarified the potential for a lesser-known Vitamin B3 called Nicotinamide Riboside that is available in selected foods, and possibly available to humans by supplements. It has properties that are insulin sensitizing, enhancing to exercise, resisting to negative effects of high-fat diet, and neuroprotecting.
Peter Belenky - One of the best experts on this subject based on the ideXlab platform.
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identification of isn1 and sdt1 as glucose and vitamin regulated Nicotinamide mononucleotide and nicotinic acid mononucleotide 5 nucleotidases responsible for production of Nicotinamide Riboside and nicotinic acid Riboside
Journal of Biological Chemistry, 2009Co-Authors: Katrina L. Bogan, Peter Belenky, Charles R. Evans, Peng Song, Charles F. Burant, Robert T. Kennedy, Charles BrennerAbstract: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.
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Identification of Isn1 and Sdt1 as Glucose- and Vitamin-regulated Nicotinamide Mononucleotide and Nicotinic Acid Mononucleotide 5′-Nucleotidases Responsible for Production of Nicotinamide Riboside and Nicotinic Acid Riboside
The Journal of biological chemistry, 2009Co-Authors: Katrina L. Bogan, Peter Belenky, Charles R. Evans, Peng Song, Charles F. Burant, Robert T. Kennedy, Charles BrennerAbstract: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.
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Nicotinamide Riboside and nicotinic acid Riboside salvage in fungi and mammals. Quantitative basis for Urh1 and purine nucleoside phosphorylase function in NAD+ metabolism.
The Journal of biological chemistry, 2008Co-Authors: Peter Belenky, Kathryn C. Christensen, Francesca S. Gazzaniga, Alexandre A. Pletnev, Charles BrennerAbstract:NAD+ is a co-enzyme for hydride transfer enzymes and an essential substrate of ADP-ribose transfer enzymes and sirtuins, the type III protein lysine deacetylases related to yeast Sir2. Supplementation of yeast cells with Nicotinamide Riboside extends replicative lifespan and increases Sir2-dependent gene silencing by virtue of increasing net NAD+ synthesis. Nicotinamide Riboside elevates NAD+ levels via the Nicotinamide Riboside kinase pathway and by a pathway initiated by splitting the nucleoside into a Nicotinamide base followed by Nicotinamide salvage. Genetic evidence has established that uridine hydrolase, purine nucleoside phosphorylase, and methylthioadenosine phosphorylase are required for Nrk-independent utilization of Nicotinamide Riboside in yeast. Here we show that mammalian purine nucleoside phosphorylase but not methylthioadenosine phosphorylase is responsible for mammalian Nicotinamide Riboside kinase-independent Nicotinamide Riboside utilization. We demonstrate that so-called uridine hydrolase is 100-fold more active as a Nicotinamide Riboside hydrolase than as a uridine hydrolase and that uridine hydrolase and mammalian purine nucleoside phosphorylase cleave nicotinic acid Riboside, whereas the yeast phosphorylase has little activity on nicotinic acid Riboside. Finally, we show that yeast nicotinic acid Riboside utilization largely depends on uridine hydrolase and Nicotinamide Riboside kinase and that nicotinic acid Riboside bioavailability is increased by ester modification.
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Saccharomyces cerevisiae YOR071C Encodes the High Affinity Nicotinamide Riboside Transporter Nrt1
Journal of Biological Chemistry, 2008Co-Authors: Peter Belenky, Tiberiu G. Moga, Charles BrennerAbstract:Abstract NAD+ is an essential coenzyme for hydride transfer enzymes and a substrate of sirtuins and other NAD+-consuming enzymes. Nicotinamide Riboside is a recently discovered eukaryotic NAD+ precursor converted to NAD+ via the Nicotinamide Riboside kinase pathway and by nucleosidase activity and Nicotinamide salvage. Nicotinamide Riboside supplementation of yeast extends replicative life span on high glucose medium. The molecular basis for Nicotinamide Riboside uptake was unknown in any eukaryote. Here, we show that deletion of a single gene, YOR071C, abrogates Nicotinamide Riboside uptake without altering nicotinic acid or Nicotinamide import. The gene, which is negatively regulated by Sum1, Hst1, and Rfm1, fully restores Nicotinamide Riboside import and utilization when resupplied to mutant yeast cells. The encoded polypeptide, Nrt1, is a predicted deca-spanning membrane protein related to the thiamine transporter, which functions as a pH-dependent facilitator with a Km for Nicotinamide Riboside of 22 μm. Nrt1-related molecules are conserved in particular fungi, suggesting a similar basis for Nicotinamide Riboside uptake.
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Nicotinamide Riboside Kinase Structures Reveal New Pathways to NAD
PLoS biology, 2007Co-Authors: Wolfram Tempel, Peter Belenky, Wael M. Rabeh, Katrina L. Bogan, Marzena Wojcik, Heather F. Seidle, Lyudmila Nedyalkova, Tianle Yang, Anthony A. Sauve, Hee-won ParkAbstract: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+.
Marie E. Migaud - One of the best experts on this subject based on the ideXlab platform.
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Equilibrative Nucleoside Transporters Mediate the Import of Nicotinamide Riboside and Nicotinic Acid Riboside into Human Cells.
International journal of molecular sciences, 2021Co-Authors: Andrey Kropotov, Marie E. Migaud, Veronika Kulikova, Kirill Nerinovski, Alexander Yakimov, Maria Svetlova, L. V. Solovjeva, Julia Sudnitsyna, Mikhail Khodorkovskiy, Mathias ZieglerAbstract:Nicotinamide Riboside (NR), a new form of vitamin B3, is an effective precursor of Nicotinamide adenine dinucleotide (NAD+) in human and animal cells. The introduction of NR into the body effectively increases the level of intracellular NAD+ and thereby restores physiological functions that are weakened or lost in experimental models of aging and various pathologies. Despite the active use of NR in applied biomedicine, the mechanism of its transport into mammalian cells is currently not understood. In this study, we used overexpression of proteins in HEK293 cells, and metabolite detection by NMR, to show that extracellular NR can be imported into cells by members of the equilibrative nucleoside transporter (ENT) family ENT1, ENT2, and ENT4. After being imported into cells, NR is readily metabolized resulting in Nam generation. Moreover, the same ENT-dependent mechanism can be used to import the deamidated form of NR, nicotinic acid Riboside (NAR). However, NAR uptake into HEK293 cells required the stimulation of its active utilization in the cytosol such as phosphorylation by NR kinase. On the other hand, we did not detect any NR uptake mediated by the concentrative nucleoside transporters (CNT) CNT1, CNT2, or CNT3, while overexpression of CNT3, but not CNT1 or CNT2, moderately stimulated NAR utilization by HEK293 cells.
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Nicotinamide Riboside-amino acid conjugates that are stable to purine nucleoside phosphorylase.
Organic & biomolecular chemistry, 2020Co-Authors: Faisal Hayat, Marie E. MigaudAbstract:The nutraceutical Nicotinamide Riboside (NR), an efficacious biosynthetic precursor to NAD, is readily metabolized by the purine nucleoside phosphorylase (PNP). Access to the PNP-stable versions of NR is difficult because the glycosidic bond of NR is easily cleaved. Unlike NR, NRH, the reduced form of NR, offers sufficient chemical stability to allow the successful functionalisation of the ribosyl-moiety. Here, we report on a series of NRH and NR derived amino acid conjugates, generated in good to excellent yields and show that O5'-esterification prevents the PNP-catalyzed phosphorolysis of these NR prodrugs.
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A reduced form of Nicotinamide Riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor
Molecular metabolism, 2019Co-Authors: Judith Giroud-gerbetant, Magali Joffraud, José L. Sanchez-garcia, Maria Pilar Giner, Angelique Cercillieux, Mikhail V. Makarov, Simona Bartova, Rubén Zapata-pérez, Riekelt H. Houtkooper, Marie E. MigaudAbstract:A decay in intracellular NAD+ levels is one of the hallmarks of physiological decline in normal tissue functions. Accordingly, dietary supplementation with NAD+ precursors can prevent, alleviate, or even reverse multiple metabolic complications and age-related disorders in diverse model organisms. Within the constellation of NAD+ precursors, Nicotinamide Riboside (NR) has gained attention due to its potent NAD+ biosynthetic effects in vivo while lacking adverse clinical effects. Nevertheless, NR is not stable in circulation, and its utilization is rate-limited by the expression of Nicotinamide Riboside kinases (NRKs). Therefore, there is a strong interest in identifying new effective NAD+ precursors that can overcome these limitations. Through a combination of metabolomics and pharmacological approaches, we describe how NRH, a reduced form of NR, serves as a potent NAD+ precursor in mammalian cells and mice. NRH acts as a more potent and faster NAD+ precursor than NR in mammalian cells and tissues. Despite the minor structural difference, we found that NRH uses different steps and enzymes to synthesize NAD+, thus revealing a new NRK1-independent pathway for NAD+ synthesis. Finally, we provide evidence that NRH is orally bioavailable in mice and prevents cisplatin-induced acute kidney injury. Our data identify a new pathway for NAD+ synthesis and classify NRH as a promising new therapeutic strategy to enhance NAD+ levels. Copyright © 2019 The Author(s). Published by Elsevier GmbH.. All rights reserved.
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a reduced form of Nicotinamide Riboside defines a new path for nad biosynthesis and acts as an orally bioavailable nad precursor
Molecular metabolism, 2019Co-Authors: Judith Giroudgerbetant, Magali Joffraud, Maria Pilar Giner, Angelique Cercillieux, Mikhail V. Makarov, Simona Bartova, Riekelt H. Houtkooper, Ruben Zapataperez, Jose L Sanchezgarcia, Marie E. MigaudAbstract:Abstract Objective A decay in intracellular NAD+ levels is one of the hallmarks of physiological decline in normal tissue functions. Accordingly, dietary supplementation with NAD+ precursors can prevent, alleviate, or even reverse multiple metabolic complications and age-related disorders in diverse model organisms. Within the constellation of NAD+ precursors, Nicotinamide Riboside (NR) has gained attention due to its potent NAD+ biosynthetic effects in vivo while lacking adverse clinical effects. Nevertheless, NR is not stable in circulation, and its utilization is rate-limited by the expression of Nicotinamide Riboside kinases (NRKs). Therefore, there is a strong interest in identifying new effective NAD+ precursors that can overcome these limitations. Methods Through a combination of metabolomics and pharmacological approaches, we describe how NRH, the reduced form of NR, serves as a potent NAD+ precursor in mammalian cells and mice. Results NRH acts as a more potent and faster NAD+ precursor than NR in mammalian cells and tissues. Despite the minor structural difference, we found that NRH uses different steps and enzymes to synthesize NAD+, thus revealing a new NRK1-independent pathway for NAD+ synthesis. Finally, we provide evidence that NRH is orally bioavailable in mice and prevents cisplatin-induced acute kidney injury. Conclusions Our data demonstrate a new pathway for NAD+ synthesis and classify NRH as a promising new therapeutic strategy to enhance NAD+ levels.
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Syntheses and chemical properties of β-Nicotinamide Riboside and its analogues and derivatives.
Beilstein journal of organic chemistry, 2019Co-Authors: Mikhail V. Makarov, Marie E. MigaudAbstract:The β-anomeric form of Nicotinamide Riboside (NR+) is a precursor for Nicotinamide adenine dinucleotide (NAD+), a redox cofactor playing a critical role in cell metabolism. Recently, it has been demonstrated that its chloride salt (NR+Cl-) has beneficial effects, and now NR+Cl- is available as a dietary supplement. Syntheses and studies of analogues and derivatives of NR+ are of high importance to unravel the role of NR+ in biochemical processes in living cells and to elaborate the next generation of NR+ derivatives and conjugates with the view of developing novel drug and food supplement candidates. This review provides an overview of the synthetic approaches, the chemical properties, and the structural and functional modifications which have been undertaken on the nicotinoyl Riboside scaffold.
Katrina L. Bogan - One of the best experts on this subject based on the ideXlab platform.
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identification of isn1 and sdt1 as glucose and vitamin regulated Nicotinamide mononucleotide and nicotinic acid mononucleotide 5 nucleotidases responsible for production of Nicotinamide Riboside and nicotinic acid Riboside
Journal of Biological Chemistry, 2009Co-Authors: Katrina L. Bogan, Peter Belenky, Charles R. Evans, Peng Song, Charles F. Burant, Robert T. Kennedy, Charles BrennerAbstract: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.
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Identification of Isn1 and Sdt1 as Glucose- and Vitamin-regulated Nicotinamide Mononucleotide and Nicotinic Acid Mononucleotide 5′-Nucleotidases Responsible for Production of Nicotinamide Riboside and Nicotinic Acid Riboside
The Journal of biological chemistry, 2009Co-Authors: Katrina L. Bogan, Peter Belenky, Charles R. Evans, Peng Song, Charles F. Burant, Robert T. Kennedy, Charles BrennerAbstract: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.
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Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition
Annual review of nutrition, 2008Co-Authors: Katrina L. Bogan, Charles BrennerAbstract:Although baseline requirements for Nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or Nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, Nicotinamide, and the newly identified NAD+ precursor, Nicotinamide Riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that Nicotinamide Riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis, we present prospects for human Nicotinamide Riboside supplementation and propose areas for future research.
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Nicotinamide Riboside Kinase Structures Reveal New Pathways to NAD
PLoS biology, 2007Co-Authors: Wolfram Tempel, Peter Belenky, Wael M. Rabeh, Katrina L. Bogan, Marzena Wojcik, Heather F. Seidle, Lyudmila Nedyalkova, Tianle Yang, Anthony A. Sauve, Hee-won ParkAbstract: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+.
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Nicotinamide Riboside Promotes Sir2 Silencing and Extends Lifespan via Nrk and Urh1/Pnp1/Meu1 Pathways to NAD+
Cell, 2007Co-Authors: Peter Belenky, Katrina L. Bogan, Frances G. Racette, Julie M. Mcclure, Jeffrey S. Smith, Charles BrennerAbstract:Although NAD(+) biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD(+) precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, Nicotinamide Riboside is a newly discovered NAD(+) precursor that is converted to Nicotinamide mononucleotide by specific Nicotinamide Riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous Nicotinamide Riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of Nicotinamide Riboside is totally dependent on increased net NAD(+) synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two Nicotinamide Riboside salvage pathways contribute to NAD(+) metabolism in the absence of Nicotinamide-Riboside supplementation. Thus, like calorie restriction in the mouse, Nicotinamide Riboside elevates NAD(+) and increases Sir2 function.