scholarly journals Nicotinamide, Nicotinamide Riboside and Nicotinic Acid—Emerging Roles in Replicative and Chronological Aging in Yeast

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 604
Author(s):  
Ivan Orlandi ◽  
Lilia Alberghina ◽  
Marina Vai
Keyword(s):  
Nicotinic Acid ◽  
Functional Decline ◽  
Model Systems ◽  
Vitamin B3 ◽  
Proliferating Cells ◽  
Yeast Saccharomyces Cerevisiae ◽  
Nad Metabolism ◽  
Chronological Aging ◽  
Nicotinamide Riboside ◽  
Metabolic Defects

Nicotinamide, nicotinic acid and nicotinamide riboside are vitamin B3 precursors of NAD+ in the human diet. NAD+ has a fundamental importance for cellular biology, that derives from its essential role as a cofactor of various metabolic redox reactions, as well as an obligate co-substrate for NAD+-consuming enzymes which are involved in many fundamental cellular processes including aging/longevity. During aging, a systemic decrease in NAD+ levels takes place, exposing the organism to the risk of a progressive inefficiency of those processes in which NAD+ is required and, consequently, contributing to the age-associated physiological/functional decline. In this context, dietary supplementation with NAD+ precursors is considered a promising strategy to prevent NAD+ decrease and attenuate in such a way several metabolic defects common to the aging process. The metabolism of NAD+ precursors and its impact on cell longevity have benefited greatly from studies performed in the yeast Saccharomyces cerevisiae, which is one of the most established model systems used to study the aging processes of both proliferating (replicative aging) and non-proliferating cells (chronological aging). In this review we summarize important aspects of the role played by nicotinamide, nicotinic acid and nicotinamide riboside in NAD+ metabolism and how each of these NAD+ precursors contribute to the different aspects that influence both replicative and chronological aging. Taken as a whole, the findings provided by the studies carried out in S. cerevisiae are informative for the understanding of the complex dynamic flexibility of NAD+ metabolism, which is essential for the maintenance of cellular fitness and for the development of dietary supplements based on NAD+ precursors.

scholarly journals Equilibrative Nucleoside Transporters Mediate the Import of Nicotinamide Riboside and Nicotinic Acid Riboside into Human Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1391
Author(s):  
Andrey Kropotov ◽  
Veronika Kulikova ◽  
Kirill Nerinovski ◽  
Alexander Yakimov ◽  
Maria Svetlova ◽  
...  
Keyword(s):  
Nicotinic Acid ◽  
Mammalian Cells ◽  
Experimental Models ◽  
The Body ◽  
Nucleoside Transporters ◽  
Hek293 Cells ◽  
Nucleoside Transporter ◽  
Vitamin B3 ◽  
Animal Cells ◽  
Nicotinamide Riboside

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.

Nicotinamide adenine dinucleotide metabolism in plants. I. Intermediates of biosynthesis in wheat leaves and the effect of benzimidazole

1970 ◽  
Vol 48 (12) ◽  
pp. 2267-2278 ◽  
Author(s):  
H. R. Godavari ◽  
E. R. Waygood
Keyword(s):  
Nicotinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Triticum Aestivum L ◽  
Total Radioactivity ◽  
Significant Loss ◽  
Nicotinamide Adenine ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Wheat Leaves

Leaves of wheat (Triticum aestivum L. var. Selkirk) were incubated with nicotinic acid-7-14C and nicotinamide-7-14C for varying time periods from 5 min to 12 h. Aliquots of alcoholic extracts of leaves were subjected to paper chromatography and radioautography to isolate the intermediates of the synthesis and breakdown of nicotinamide adenine dinucleotide. Nine compounds were isolated quantitatively and identified as intermediates in the pathway of NAD metabolism. All the intermediates were labeled rapidly and the rapidity of labeling became a problem in rigorously proving the sequential operation of the pathway. The results indicate that the Preiss-Handler pathway: nicotinic acid→nicotinic acid mononucleotide→nicotinic acid adenine dinucleotide→NAD operates in wheat leaves. The degradation of NAD proceeded from NAD→nicotinamide mononucleotide→nicotinamide riboside→nicotinamide. Deamidation of the nicotinamide to nicotinic acid initiated a fresh cycle of biosynthesis. The total radioactivity recovered in the intermediates indicates that no measurable amount was lost to other metabolic pathways. Nicotinamide is recovered without significant loss and recycled. The rapid appearance of labeled nicotinamide indicates a possible interconversion of nicotinic acid and nicotinamide. About 80% of the radioactivity accumulated was present in trigonelline which is considered, on the basis of other evidence, to be a non-toxic form of nicotinic acid. Benzimidazole treatment of the leaves increased the incorporation of 14C into NADP.

scholarly journals Degradation of Extracellular NAD+ Intermediates in Cultures of Human HEK293 Cells

Metabolites ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 293 ◽  
Author(s):  
Veronika Kulikova ◽  
Konstantin Shabalin ◽  
Kirill Nerinovski ◽  
Alexander Yakimov ◽  
Maria Svetlova ◽  
...  
Keyword(s):  
Cell Culture ◽  
Nicotinic Acid ◽  
Culture Medium ◽  
Cultured Cells ◽  
Culture Conditions ◽  
Hek293 Cells ◽  
Vitamin B3 ◽  
Serum Free ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide

Nicotinamide adenine dinucleotide (NAD) is an essential redox carrier, whereas its degradation is a key element of important signaling pathways. Human cells replenish their NAD contents through NAD biosynthesis from extracellular precursors. These precursors encompass bases nicotinamide (Nam) and nicotinic acid and their corresponding nucleosides nicotinamide riboside (NR) and nicotinic acid riboside (NAR), now collectively referred to as vitamin B3. In addition, extracellular NAD+ and nicotinamide mononucleotide (NMN), and potentially their deamidated counterparts, nicotinic acid adenine dinucleotide (NAAD) and nicotinic acid mononucleotide (NAMN), may serve as precursors of intracellular NAD. However, it is still debated whether nucleotides enter cells directly or whether they are converted to nucleosides and bases prior to uptake into cells. Here, we studied the metabolism of extracellular NAD+ and its derivatives in human HEK293 cells using normal and serum-free culture medium. Using medium containing 10% fetal bovine serum (FBS), mono- and dinucleotides were degraded to the corresponding nucleosides. In turn, the nucleosides were cleaved to their corresponding bases. Degradation was also observed in culture medium alone, in the absence of cells, indicating that FBS contains enzymatic activities which degrade NAD+ intermediates. Surprisingly, NR was also rather efficiently hydrolyzed to Nam in the absence of FBS. When cultivated in serum-free medium, HEK293 cells efficiently cleaved NAD+ and NAAD to NMN and NAMN. NMN exhibited rather high stability in cell culture, but was partially metabolized to NR. Using pharmacological inhibitors of plasma membrane transporters, we also showed that extracellular cleavage of NAD+ and NMN to NR is a prerequisite for using these nucleotides to maintain intracellular NAD contents. We also present evidence that, besides spontaneous hydrolysis, NR is intensively metabolized in cell culture by intracellular conversion to Nam. Our results demonstrate that both the cultured cells and the culture medium mediate a rather active conversion of NAD+ intermediates. Consequently, in studies of precursor supplementation and uptake, the culture conditions need to be carefully defined.

scholarly journals The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolism

2018 ◽  
Vol 61 (3) ◽  
pp. R107-R121 ◽  
Author(s):  
Rachel S Fletcher ◽  
Gareth G Lavery
Keyword(s):  
Metabolic Disease ◽  
Vitamin B3 ◽  
Nad Metabolism ◽  
Regulatory Pathways ◽  
Nicotinamide Riboside ◽  
Systemic Level ◽  
Salvage Pathways ◽  
Precursor Molecules ◽  
Kinase Pathway ◽  
Intense Research

The concept of replenishing or elevating NAD+availability to combat metabolic disease and ageing is an area of intense research. This has led to a need to define the endogenous regulatory pathways and mechanisms cells and tissues utilise to maximise NAD+availability such that strategies to intervene in the clinical setting are able to be fully realised. This review discusses the importance of different salvage pathways involved in metabolising the vitamin B3 class of NAD+precursor molecules, with a particular focus on the recently identified nicotinamide riboside kinase pathway at both a tissue-specific and systemic level.

scholarly journals Microbial NAD Metabolism: Lessons from Comparative Genomics

2009 ◽  
Vol 73 (3) ◽  
pp. 529-541 ◽  
Author(s):  
Francesca Gazzaniga ◽  
Rebecca Stebbins ◽  
Sheila Z. Chang ◽  
Mark A. McPeek ◽  
Charles Brenner
Keyword(s):  
Nicotinic Acid ◽  
De Novo ◽  
Strictly Aerobic ◽  
Bacterial Dna ◽  
Nad Metabolism ◽  
Dna Ligases ◽  
Nicotinamide Riboside ◽  
Nad Synthesis ◽  
Biochemical Genetic ◽  
Lysine Deacetylases

SUMMARY NAD is a coenzyme for redox reactions and a substrate of NAD-consuming enzymes, including ADP-ribose transferases, Sir2-related protein lysine deacetylases, and bacterial DNA ligases. Microorganisms that synthesize NAD from as few as one to as many as five of the six identified biosynthetic precursors have been identified. De novo NAD synthesis from aspartate or tryptophan is neither universal nor strictly aerobic. Salvage NAD synthesis from nicotinamide, nicotinic acid, nicotinamide riboside, and nicotinic acid riboside occurs via modules of different genes. Nicotinamide salvage genes nadV and pncA, found in distinct bacteria, appear to have spread throughout the tree of life via horizontal gene transfer. Biochemical, genetic, and genomic analyses have advanced to the point at which the precursors and pathways utilized by a microorganism can be predicted. Challenges remain in dissecting regulation of pathways.

P6274Role of the nicotinamide riboside kinase 2 in NAD metabolism in the heart in basal and pathological condition

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Deloux ◽  
C Tannous ◽  
A Karoui ◽  
N Mougenot ◽  
Z Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Function ◽  
Pathological Condition ◽  
Control Diet ◽  
Functional Improvement ◽  
Wild Type ◽  
Vitamin B3 ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Beneficial Effects

Abstract Background NAD is a major coenzyme in energy metabolism and a substrate for SIRT1 and PARP1 enzymes involved in the response to energy and oxidative stress. We have shown the beneficial effects of nicotinamide riboside (NR), a new type of vitamin B3, on cardiac function and remodelling in a mouse model of dilated cardiomyopathy (DCM) triggered by deletion of the SRF transcription factor in the heart (Srf-HKO) (1). This functional improvement correlated with protection of NAD metabolism and a robust increase in cardiac expression of the Nicotinamide Riboside Kinase 2 (NMRK2) that phosphorylates NR to generate nicotinamide mononucleotide (NMN), an immediate precursor of NAD. Purpose We aim to understand the role of the NMRK2-mediated NAD biosynthetic pathway in the heart at baseline and in the DCM context. Methods We generated Nmrk2-KO mice that we bred with Srf-HKO to generate double KO mice (db-KO). We analysed cardiac function and remodelling by echocardiography and quantified myocardial NAD levels at baseline and following NR supplementation in food. Results Nmrk2KO mice developed a progressive eccentric remodelling of LV and decline in EF with aging. At 24-mo, we observed a reduction of myocardial NAD levels (−40% compared to wild type, p<0.05) and of LVEF (61%, SD 6.3% in Nmrk2-KO vs 78%, SD 1.5% in WT, p<0.05). To assess the contribution of cardiac Nmrk2 induction to NR response in DCM, we compared SrfH-KO and db-KO mice fed with control diet (CD) or NR supplemented diet for 40 days starting at young age (2-mo). NR reduced the extent of LV eccentric remodelling and drop in EF as well as the thinning of the LV posterior wall in both genotypes (2-way ANOVA, diet effect, p<0.01). Myocardial NAD levels were more reduced in db-KO mice under CD diet (−22% compared to control mice, p<0.05) than in Srf-HKO mice (−11%, non-significant), when we previously showed a 25% drop in myocardial NAD in aged SrfHKO mice (1). NR partially preserved cardiac NAD pool in db-KOmice (−10% compared to controls, non-significant). Parallel pathways for NMN synthesis were studied. Nampt gene expression was significantly repressed in db-KO mice fed with CD or NR diet compared to control mice (−50% in average, p<0.01), when there was only a trend toward lower expression in SrfHKO mice (−40% in average, p>0.05). Nmrk1 gene expression trended to increase in all groups compared to wild-type control mice. Conclusion We show that NMRK2 pathway plays a role in the maintenance of basal cardiac function and NAD levels when relying on the endogenous myocardial NR pool. In contrast, the beneficial effect of a therapeutic dose of NR is not affected by the lack of NMRK2 suggesting compensation by NMRK1 in the heart and/or that NR beneficial effects on cardiac function could be mediated through its action on systemic metabolism. Aging appears as an aggravating factor for the loss of myocardial NAD coenzyme in DCM. Acknowledgement/Funding Agence Nationale pour la Recherche, Fondation de France

scholarly journals Stability constants of Nicotinic acid (vitamin B3) complexes with transition metal ions

2020 ◽  
Vol 2 (7) ◽  
pp. 136-138
Author(s):  
Shalini Dengle ◽  
Mahesh Shivoorkar ◽  
Momin Nishad Parvin ◽  
Ayesha Nuzat Durrani
Keyword(s):  
Transition Metal ◽  
Nicotinic Acid ◽  
Metal Ions ◽  
Stability Constants ◽  
Transition Metal Ions ◽  
Vitamin B3
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