Nicotinamide riboside

Last updated
Nicotinamide riboside
Nicotinamide-beta-riboside.svg
Nicotinamideriboside.png
Names
IUPAC name
3-Carbamoyl-1-(β-D-ribofuranosyl)pyridin-1-ium
Systematic IUPAC name
3-Carbamoyl-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyridin-1-ium
Other names
1-(β-D-Ribofuranosyl)nicotinamide; N-Ribosylnicotinamide
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
UNII
  • InChI=1S/C11H14N2O5/c12-10(17)6-2-1-3-13(4-6)11-9(16)8(15)7(5-14)18
  • c1cc(c[n+](c1)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O)C(=O)N
Properties
C11H15N2O5+
Molar mass 255.25 g/mol
Melting point Complete thermal degradation occurs above 130°C (chloride salt) [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Nicotinamide riboside (NR, SR647) is a pyridine-nucleoside and a form of vitamin B3. It functions as a precursor to nicotinamide adenine dinucleotide, or NAD+, [2] through a two-step and a three-step pathway. [3]

Contents

Chemistry

While the molecular weight of nicotinamide riboside is 255.25 g/mol, [4] that of its chloride salt is 290.70 g/mol. [5] [6] As such, 100 mg of nicotinamide riboside chloride provides 88 mg of nicotinamide riboside.[ citation needed ]

Stability and degradation

NRCl is susceptible to degradation through both thermal decomposition and base-catalyzed hydrolysis:

These properties emphasize the need for careful formulation strategies to ensure NRCl's stability during storage, processing, and delivery.[ citation needed ]

History

Nicotinamide riboside (NR) has been identified as an NAD precursor, involved in salvage NAD synthesis in both bacteria and eukaryotes. [7] In bacteria, it was first described in 1944 as a necessary growth factor for the culture of Haemophilus influenza , H. influenza was identified as requiring both X factor (hemin) and V factor (NAD) to grow. [8] V factor, purified from blood, was shown to exist in three forms: Nicotinamide adenine dinucleotide (NAD+), NMN and NR. NR was the compound that led to the most rapid growth of the H. influenza bacterium. [9] [7]

H. influenza cannot grow on nicotinic acid (NA), nicotinamide (NAM), or amino acids such as tryptophan (Trp) or aspartic acid (Asp), which were the previously known precursors of NAD+. [7] [10] H. influenza depends entirely on salvage of NAD precursors from other cells in its environment. [9]

The identification of Nicotinamide riboside (NR) as an NAD precursor in eukaryotes developed out of the study of pellagra. [11] Pellagra was the first disease to be associated with NAD+ deficiency. [12] It was linked to nutritional deficiency by Joseph Goldberger in 1914, and to deficiency of niacin (vitamin B3) by Conrad Elvehjem in 1937. NAD+ (then called coenzyme I) was shown to be extremely low in cases of pellagra, and NA and NAM were identified as molecular precursors in rebuilding NAD+ levels. Pellagra is now understood as a severe, chronic depletion of NAD+, which can be treated through diet. [11]

Subsequent studies of NAD+ metabolism have identified regulatory pathways used by cells and tissues to maintain NAD+ availability. NAD+ and its precursors nicotinic acid (NA) and nicotinamide (NAM) have been shown to be vital cofactors in cellular oxidation/reduction reactions and ATP synthesis. Classic NAD+ synthesis pathways characterized in eukaryotes include an eight-step de novo pathway from Trp and two pathways using the NAD+ precursors NA and NAM: a three-step NA-based pathway known as the Preiss-Handler pathway; and an NAM-based pathway involving the enzyme Nicotinamide phosphoribosyltransferase (NAMPT) and the formation of nicotinamide mononucleotide (NMN). [11] [13] [14]

In 2004, a previously unknown pathway was reported when nicotinamide riboside (NR) was identified as an additional NAD+ precursor in eukaryotes. [11] [13] [14] NR is now recognized as a form of vitamin B3 [15] which can be found in both cow and human milk. [11] [16] Once internalized into a cell, NR is rapidly phosphorylated by the activity of nicotinamide riboside kinase enzymes (NRK1 and NRK2) to form nicotinamide mononucleotide (NMN), bypassing the previously known biosynthetic routes to NAD+ production. NMN is then converted to NAD+ by NMN-adenylyltransferase (NMNAT). [13]

Research in mammals indicates that NRK1 is a cytosolic protein, encoded by the Nmrk1 gene. It is found in most tissues but predominantly in the liver and kidney. The NRK2 protein may be related to muscle tissue including cardiac muscle. It is encoded by the Nmrk2 gene and appears to be more highly expressed in cases of metabolic stress or cellular damage. [11] [13] [14] Since different types of tissues display differing concentrations of NR and NRKs, it is likely that NR utilization will vary in different tissues. [3] [13]

Metabolic studies indicate that NAD+, once considered a stable molecule, is continuously turned over and used, requiring tight regulation to maintain metabolic homeostasis. NR utilization in mammals may involve both exogenous dietary sources and endogenous salvage processes that recycle intermediates. NR metabolism and the interactions of different NAD+ pathways continue to be studied. The NAM and NR pathways involve an amide group and are referred to as 'amidated' pathways. The pathways for de novo synthesis from tryptophan and from NA salvage are 'deamidated' pathways, which share a rate-limiting amidation enzyme NADsynthase1 (NADSYN). [13] [11] Disruptions or imbalances in NAD+ metabolism have been observed in many disease conditions, and the possibility of restoring NAD+ levels by administering NAD+ precursors is an area of interest for researchers. [11] [12] [13]

Biosynthesis

Nicotinamide riboside (NR) is now known to be an NAD+ precursor, involved in the biosynthetic pathways that convert B3 vitamins into NAD+. NAD+ is primarily synthesized in mammals de novo from tryptophan, through the Priess-Handler pathway from nicotinic acid (NA) or via a salvage pathway from nicotinamide (NAM). [17]

NRK1/2 mediated pathway from NR to NAD+ NRK1 and NRK2 mediated biosynthesis pathway from NR to NAD+.png
NRK1/2 mediated pathway from NR to NAD+

Nicotinamide riboside (NR) is utilized through an additional pathway involving phosphorylation by the nicotinamide riboside kinase enzymes (NRK1 and NRK2). [17] [13] In yeasts, NR has also been shown to be degraded by the nucleosidases Pnp1, Urh1 and Meu1, before being converted to NAD⁺ via the Preiss-Handler pathway and the action of the nicotinamidase Pnc1. [3] [10]

Commercialization

ChromaDex licensed patents in July 2012, and began to develop a process to bring NR to market as TruNiagen. [18] ChromaDex has been in a patent dispute with Elysium Health over the rights to nicotinamide riboside supplements since 2016. [19]

Safety designations

In 2016, the U.S. Food and Drug Administration (FDA) has granted Generally recognized as safe (GRAS) status to ChromaDex for its preparation of nicotinamide riboside chloride (NRC, Niagen™). [5] [20] [3] It was designated a new dietary ingredient (NDI) for use in dietary supplements by the U.S. Food and Drug Administration in 2015 and 2017. It was listed in Health Canada's Licensed Natural Health Products Database (LNHPD) in 2018. The European Union has granted NRC a "New dietary ingredient" designation as a novel food pursuant to Regulation (EU) 2015/2283, as of 2019. It was authorized for use in food supplements by the EU in 2020. The EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) considered it as safe as pure nicotinamide for use in food for special medical purposes (FSMP) and total diet replacement for weight control (TDRWC) in adults as of 2021 but noted that further investigation would be required to establish safety for some other types of use. [21] The Australian government has given nicotinamide riboside chloride a positive listing under the compositional guidelines of its Therapeutic Goods Administration (TGA). [22]

See also

Related Research Articles

<span class="mw-page-title-main">Nicotinamide</span> Dietary supplement and medication

Niacinamide or nicotinamide is a form of vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used orally (swallowed by mouth) to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) may be used for this purpose, niacinamide has the benefit of not causing skin flushing. As a cream, it is used to treat acne, and has been observed in clinical studies to improve the appearance of aging skin by reducing hyperpigmentation and redness. It is a water-soluble vitamin. Niacinamide is the supplement name, while nicotinamide is the scientific name.

<span class="mw-page-title-main">Niacin</span> Organic compound and a form of vitamin B3

Niacin, also known as nicotinic acid, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variety of whole and processed foods, with highest contents in fortified packaged foods, meat, poultry, red fish such as tuna and salmon, lesser amounts in nuts, legumes and seeds. Niacin as a dietary supplement is used to treat pellagra, a disease caused by niacin deficiency. Signs and symptoms of pellagra include skin and mouth lesions, anemia, headaches, and tiredness. Many countries mandate its addition to wheat flour or other food grains, thereby reducing the risk of pellagra.

<span class="mw-page-title-main">Adenine</span> Chemical compound in DNA and RNA

Adenine is a purine nucleotide base. It is one of the four nucleobases in the nucleic acids of DNA, the other three being guanine (G), cytosine (C), and thymine (T). Adenine derivatives have various roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate (ATP) and the cofactors nicotinamide adenine dinucleotide (NAD), flavin adenine dinucleotide (FAD) and Coenzyme A. It also has functions in protein synthesis and as a chemical component of DNA and RNA. The shape of adenine is complementary to either thymine in DNA or uracil in RNA.

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide phosphate</span> Chemical compound

Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADPH as a reducing agent ('hydrogen source'). NADPH is the reduced form, whereas NADP+ is the oxidized form. NADP+ is used by all forms of cellular life. NADP+ is essential for life because it is needed for cellular respiration.

DNA ligase (NAD+) (EC 6.5.1.2, polydeoxyribonucleotide synthase (NAD+), polynucleotide ligase (NAD+), DNA repair enzyme, DNA joinase, polynucleotide synthetase (nicotinamide adenine dinucleotide), deoxyribonucleic-joining enzyme, deoxyribonucleic ligase, deoxyribonucleic repair enzyme, deoxyribonucleic joinase, DNA ligase, deoxyribonucleate ligase, polynucleotide ligase, deoxyribonucleic acid ligase, polynucleotide synthetase, deoxyribonucleic acid joinase, DNA-joining enzyme, polynucleotide ligase (nicotinamide adenine dinucleotide)) is an enzyme with systematic name poly(deoxyribonucleotide):poly(deoxyribonucleotide) ligase (AMP-forming, NMN-forming). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Heterocyclic amine</span> Any heterocyclic compound having at least one nitrogen heteroatom

Heterocyclic amines, also sometimes referred to as HCAs, are chemical compounds containing at least one heterocyclic ring, which by definition has atoms of at least two different elements, as well as at least one amine (nitrogen-containing) group. Typically it is a nitrogen atom of an amine group that also makes the ring heterocyclic, though compounds exist in which this is not the case. The biological functions of heterocyclic amines vary, including vitamins and carcinogens. Carcinogenic heterocyclic amines are created by high temperature cooking of meat and smoking of plant matter like tobacco. Some well known heterocyclic amines are niacin, nicotine, and the nucleobases that encode genetic information in DNA.

Malate dehydrogenase (NADP<sup>+</sup>) Enzyme class

In enzymology, a malate dehydrogenase (NADP+) (EC 1.1.1.82) is an enzyme that catalyzes the chemical reaction

In enzymology, a cis-1,2-dihydrobenzene-1,2-diol dehydrogenase (EC 1.3.1.19) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Nicotinamide phosphoribosyltransferase</span> Human protein and coding gene

Nicotinamide phosphoribosyltransferase, formerly known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin for its extracellular form (eNAMPT), is an enzyme that in humans is encoded by the NAMPT gene. The intracellular form of this protein (iNAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide to nicotinamide mononucleotide (NMN) which is responsible for most of the NAD+ formation in mammals. iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present. eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4, that promotes B cell maturation, and that inhibits neutrophil apoptosis.

<span class="mw-page-title-main">Nicotinamide-nucleotide adenylyltransferase</span>

In enzymology, nicotinamide-nucleotide adenylyltransferase (NMNAT) (EC 2.7.7.1) are enzymes that catalyzes the chemical reaction

<span class="mw-page-title-main">NMNAT1</span> Protein-coding gene in the species Homo sapiens

Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is an enzyme that in humans is encoded by the nmnat1 gene. It is a member of the nicotinamide-nucleotide adenylyltransferases (NMNATs) which catalyze nicotinamide adenine dinucleotide (NAD) synthesis.

<span class="mw-page-title-main">1-Methylnicotinamide</span> Ion

1-Methylnicotinamide (trigonellamide) is a prototypic organic cation. 1-Methylnicotinamide is the methylated amide of Nicotinamide (niacinamide, vitamin B3).

Charles Brenner is the inaugural Alfred E Mann Family Foundation Chair of the Department of Diabetes & Cancer Metabolism at the Beckman Research Institute of the City of Hope National Medical Center. Brenner previously held the Roy J. Carver Chair in Biochemistry and was head of biochemistry at the University of Iowa.

The Nicotinamide Ribonucleoside (NR) Uptake Permease (PnuC) Family is a family of transmembrane transporters that is part of the TOG superfamily. Close PnuC homologues are found in a wide range of Gram-negative and Gram-positive bacteria, archaea and eukaryotes.

<span class="mw-page-title-main">Nicotinamide mononucleotide</span> Chemical compound

Nicotinamide mononucleotide is a nucleotide derived from ribose, nicotinamide, nicotinamide riboside and niacin. In humans, several enzymes use NMN to generate nicotinamide adenine dinucleotide (NADH). In mice, it has been proposed that NMN is absorbed via the small intestine within 10 minutes of oral uptake and converted to nicotinamide adenine dinucleotide (NAD+) through the Slc12a8 transporter. However, this observation has been challenged, and the matter remains unsettled.

Vitamin B<sub>3</sub> Class of chemically related vitamers

Vitamin B3, colloquially referred to as niacin, is a vitamin family that includes three forms, or vitamers: niacin (nicotinic acid), nicotinamide (niacinamide), and nicotinamide riboside. All three forms of vitamin B3 are converted within the body to nicotinamide adenine dinucleotide (NAD). NAD is required for human life and people are unable to make it within their bodies without either vitamin B3 or tryptophan. Nicotinamide riboside was identified as a form of vitamin B3 in 2004.

<span class="mw-page-title-main">SARM1</span> Protein-coding gene in the species Homo sapiens

Sterile alpha and TIR motif containing 1 Is an enzyme that in humans is encoded by the SARM1 gene. It is the most evolutionarily conserved member of the Toll/Interleukin receptor-1 (TIR) family. SARM1's TIR domain has intrinsic NADase enzymatic activity that is highly conserved from archaea, plants, nematode worms, fruit flies, and humans. In mammals, SARM1 is highly expressed in neurons, where it resides in both cell bodies and axons, and can be associated with mitochondria.

<span class="mw-page-title-main">CD38-IN-78c</span> Chemical compound

CD38-IN-78c is a drug which acts as a potent and selective inhibitor of the glycoprotein enzyme CD38. In animal studies it boosts levels of nicotinamide adenine dinucleotide (NAD+) in tissues via inhibition of CD38 mediated breakdown of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), and has been shown to ameliorate metabolic dysfunction associated with the aging process. It also has potential therapeutic application in the treatment of asthma.

<span class="mw-page-title-main">Dihydronicotinamide mononucleotide</span> Chemical compound

NMNH, also known as reduced nicotinamide mononucleotide. Both NMNH and NMN increase NAD+ levels in the body. NAD+ is a universal coenzyme that plays vital roles in nearly all living organisms functioning in various biological processes such as metabolism, cell signaling, gene regulation, and DNA repair.

References

  1. 1 2 3 Campbell, MT; Jones, DS; Andrews, GP; Li, S (2019). "Understanding the physicochemical properties and degradation kinetics of nicotinamide riboside chloride". Food & Nutrition Research. 63: 3419. doi:10.29219/fnr.v63.3419. PMC   6878970 . PMID   31807125.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ↑ Bogan, KL; Brenner, C (2008). "Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition". Annu. Rev. Nutr. 28: 115–130. doi:10.1146/annurev.nutr.28.061807.155443. PMID   18429699.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. 1 2 3 4 Mehmel, M; Jovanović, N; Spitz, U (31 May 2020). "Nicotinamide Riboside-The Current State of Research and Therapeutic Uses". Nutrients. 12 (6): 1616. doi: 10.3390/nu12061616 . PMC   7352172 . PMID   32486488.
  4. ↑ "Nicotinamide riboside". pubchem.ncbi.nlm.nih.gov. Archived from the original on 2017-02-20. Retrieved 2017-02-20.
  5. 1 2 "GRAS Notices, GRN No. 635". www.accessdata.fda.gov. Archived from the original on 11 February 2017. Retrieved 18 February 2019.
  6. ↑ "Spherix/ChromaDex GRAS submission" (PDF). FDA.gov. Archived (PDF) from the original on 4 March 2017. Retrieved 18 February 2019.
  7. 1 2 3 Gazzaniga, F; et al. (September 2009). "Microbial NAD metabolism: lessons from comparative genomics". Microbiology and Molecular Biology Reviews. 73 (3): 529–41. doi:10.1128/MMBR.00042-08. PMC   2738131 . PMID   19721089.
  8. ↑ World Health Organization; Centers for Disease Control and Prevention (2011). "Chapter 9 Identification and Characterization of Haemophilus influenzae". Laboratory Methods for the Diagnosis of Meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae (PDF) (Second ed.). Geneva, Switzerland: WHO Press, World Health Organization. pp. 87–104. Archived (PDF) from the original on 2023-02-12. Retrieved 2023-02-12.
  9. 1 2 Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. doi:10.1128/JB.47.6.535-550.1944. PMC   373952 . PMID   16560803.
  10. 1 2 Belenky, P.; et al. (2007). "NAD+ Metabolism in Health and Disease". Trends in Biochemical Sciences. 32 (1): 12–19. doi:10.1016/j.tibs.2006.11.006. PMID   17161604.
  11. 1 2 3 4 5 6 7 8 Cercillieux, A; Ciarlo, E; Canto, C (2022-08-02). "Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations". Cellular and Molecular Life Sciences. 79 (8): 463. doi:10.1007/s00018-022-04499-5. ISSN   1420-9071. PMC   9345839 . PMID   35918544.
  12. 1 2 Katsyuba, E; Romani, M; Hofer, D; Auwerx, J (January 2020). "NAD(+) homeostasis in health and disease". Nature Metabolism. 2 (1): 9–31. doi:10.1038/s42255-019-0161-5. ISSN   2522-5812. PMID   32694684. S2CID   214277961. Archived from the original on 11 November 2022. Retrieved 6 February 2023.
  13. 1 2 3 4 5 6 7 8 Fletcher RS, Lavery GG (2018). "The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolism". Journal of Molecular Endocrinology . 61 (1): R107–R121. doi:10.1530/JME-18-0085. PMC   6145238 . PMID   30307159.
  14. 1 2 3 Reiten, OK; Wilvang, MA; Mitchell, SJ; Hu, Z; Fang, EF (October 2021). "Preclinical and clinical evidence of NAD(+) precursors in health, disease, and ageing". Mechanisms of Ageing and Development. 199: 111567. doi:10.1016/j.mad.2021.111567. hdl: 20.500.11850/506217 . PMID   34517020. S2CID   237459655. Archived from the original on 2023-02-13. Retrieved 2023-02-13.
  15. ↑ Chi, Y; Sauve, AA (November 2013). "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. 16 (6): 657–61. doi:10.1097/MCO.0b013e32836510c0. PMID   24071780. S2CID   205782942. Archived from the original on 2023-02-13. Retrieved 2023-02-13.
  16. ↑ Ummarino, S; Mozzon, M; Zamporlini, F; Amici, A; Mazzola, F; Orsomando, G; Ruggieri, S; Raffaelli, N (15 April 2017). "Simultaneous quantitation of nicotinamide riboside, nicotinamide mononucleotide and nicotinamide adenine dinucleotide in milk by a novel enzyme-coupled assay". Food Chemistry. 221: 161–168. doi:10.1016/j.foodchem.2016.10.032. PMID   27979136. Archived from the original on 16 February 2023. Retrieved 16 February 2023.
  17. 1 2 McReynolds, MR; Chellappa, K; Baur, JA (22 February 2020). "Age-related NAD(+) decline". Experimental Gerontology. 134: 110888. doi:10.1016/j.exger.2020.110888. PMC   7442590 . PMID   32097708.
  18. ↑ "ChromaDex Licenses Exclusive Patent Rights for Nicotinamide Riboside (NR) Vitamin Technologies". 2012-07-16. Archived from the original on 2019-02-15. Retrieved 15 February 2019.
  19. ↑ Bomgardner, Melody M. (2018). "Firms feud over purported age-fighting molecule". Chemical & Engineering News . 96 (33). Archived from the original on 2022-11-16. Retrieved 2022-11-16.
  20. ↑ "GRAS Notice (GRN) No. 635" (PDF). FDA. Archived (PDF) from the original on 2 January 2023. Retrieved 15 February 2023.
  21. ↑ Turck, D; et al. (November 2021). "Extension of use of nicotinamide riboside chloride as a novel food pursuant to Regulation (EU) 2015/2283". EFSA Journal. 19 (11): e06843. doi:10.2903/j.efsa.2021.6843. PMC   8586847 . PMID   34804232.
  22. ↑ "Nicotinamide riboside chloride". Department of Health and Aged Care, Commonwealth of Australia. Archived from the original on 16 February 2023. Retrieved 16 February 2023.
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