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Nicotinamide mononucleotide

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Nicotinamide mononucleotide
Names
IUPAC name
3-Carbamoyl-1-(5-O-phosphono-β-D-ribofuranosyl)pyridin-1-ium
Systematic IUPAC name
[(2R,3S,4R,5R)-5-(3-Carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl hydrogen phosphate
Other names
  • Nicotinamide ribonucleoside 5′-phosphate
  • Nicotinamide D-ribonucleotide
  • β-Nicotinamide ribose monophosphate
  • Nicotinamide nucleotide
Identifiers
3D model (JSmol)
3570187
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.012.851 Edit this at Wikidata
EC Number
  • 214-136-5
KEGG
UNII
  • InChI=1S/C11H15N2O8P/c12-10(16)6-2-1-3-13(4-6)11-9(15)8(14)7(21-11)5-20-22(17,18)19/h1-4,7-9,11,14-15H,5H2,(H3-,12,16,17,18,19)/t7-,8-,9-,11-/m1/s1
    Key: DAYLJWODMCOQEW-TURQNECASA-N
  • c1cc(c[n+](c1)[C@H]2[C@@H]([C@@H]([C@H](O2)COP(=O)(O)[O-])O)O)C(=O)N
Properties
C11H15N2O8P
Molar mass 334.221 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Nicotinamide mononucleotide ("NMN" and "β-NMN") is a nucleotide derived from ribose, nicotinamide, nicotinamide riboside and niacin.[1] In humans, several enzymes use NMN to generate nicotinamide adenine dinucleotide (NADH).[1] 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.[2] However, this observation has been challenged,[3] and the matter remains unsettled.[4]

Because NADH is a cofactor for processes inside mitochondria, for sirtuins and PARP, NMN has been studied in animal models as a potential neuroprotective and anti-aging agent.[5][6] The reversal of aging at the cellular level by inhibiting mitochondrial decay in presence of increased levels of NAD+ makes it popular among anti-aging products.[7] Dietary supplement companies have aggressively marketed NMN products, claiming those benefits.[8] However, no human studies to date have properly proven its anti-aging effects with proposed health benefits only suggested through research done in vitro or through animal models.[9] Single-dose administration of up to 500 mg was shown safe in men in a study at Keio University.[10] One 2021 clinical trial found that NMN improved muscular insulin sensitivity in prediabetic women,[11] while another found that it improved aerobic capacity in amateur runners.[12] A 2023 clinical trial showed that NMN improves performance on a six-minute walking test and a subjective general health assessment.[13]

NMN is vulnerable to extracellular degradation by CD38 enzyme,[14] which can be inhibited by compounds such as CD38-IN-78c.[15]

Dietary sources

[edit]

NMN is found in fruits and vegetables such as edamame, broccoli, cabbage, cucumber and avocado at a concentration of about 1 mg per 100g,[16][17][18] making these natural sources impractical to acquire the quantities needed to accomplish the dosing currently being investigated for NMN as a pharmaceutical.

Production

[edit]

Production of nicotinamide mononucleotide has been redacted since the latter half of 2022 by the FDA because it is under investigation as a pharmaceutical drug.[19][20]

Different expressions of NMN across human organs

[edit]

The synthesizing enzymes and consumption enzymes of NMN also exhibit tissue specificity: NMN is widely distributed in tissues and organs throughout the body and has been present in various cells since embryonic development.[20]

Potential benefits and risks

[edit]

NMN is a precursor for NAD+ biosynthesis, and NMN dietary supplementation has been demonstrated to increase NAD+ concentration and thus has the potential to mitigate aging-related disorders such as oxidative stress, DNA damage, neurodegeneration and inflammatory responses.[21] The potential benefits and risks of NMN supplementation, as of 2023, are currently under investigation.[21]

Certain enzymes are sensitive to the intracellular NMN/NAD+ ratio, such as SARM1,[22] a protein responsible for initiating cellular degeneration pathways such as MAP kinase and inducing axonal loss and neuronal death.[23][24] NMNAT is an enzyme with neurorescuing properties that functions to deplete NMN and produce NAD+, attenuating SARM1 activity and aiding neuronal survival in-vitro,[25][26] an effect that is reversed by applying exogenous NMN which promptly resumed axon destruction.[23] The similar molecule nicotinic acid mononucleotide (NaMN) opposes the activating effect of NMN on SARM1, and is a neuroprotector.[27]

References

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  1. ^ a b Roger Lee, Roger (2023). "Different Expressions of NMN Across Human Organs". American Journal of Sociology – via Frank Lee.
  2. ^ Grozio, A; Mills, KF; Yoshino, J; Bruzzone, S; Sociali, G; Tokizane, K; Lei, HC; Cunningham, R; Sasaki, Y; Migaud, ME; Imai, SI (January 2019). "Slc12a8 is a nicotinamide mononucleotide transporter". Nature Metabolism. 1 (1): 47–57. doi:10.1038/s42255-018-0009-4. PMC 6530925. PMID 31131364.
  3. ^ Schmidt, MS; Brenner, C (July 2019). "Absence of evidence that Slc12a8 encodes a nicotinamide mononucleotide transporter". Nature Metabolism. 1 (7): 660–661. doi:10.1038/s42255-019-0085-0. PMID 32694648. S2CID 203899191.
  4. ^ Chini, CCS; Zeidler, JD; Kashyap, S; Warner, G; Chini, EN (1 June 2021). "Evolving concepts in NAD+ metabolism". Cell Metabolism. 33 (6): 1076–1087. doi:10.1016/j.cmet.2021.04.003. PMC 8172449. PMID 33930322.
  5. ^ Brazill JM, Li C, Zhu Y, Zhai RG (June 2017). "+ synthase… It's a chaperone… It's a neuroprotector". Current Opinion in Genetics & Development. 44: 156–162. doi:10.1016/j.gde.2017.03.014. PMC 5515290. PMID 28445802.
  6. ^ Mills, Kathryn F.; Yoshida, Shohei; Stein, Liana R.; Grozio, Alessia; Kubota, Shunsuke; Sasaki, Yo; Redpath, Philip; Migaud, Marie E.; Apte, Rajendra S.; Uchida, Koji; Yoshino, Jun; Imai, Shin-Ichiro (13 December 2016). "Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice". Cell Metabolism. 24 (6): 795–806. doi:10.1016/j.cmet.2016.09.013. PMC 5668137. PMID 28068222.
  7. ^ Nadeeshani, Harshani; Li, Jinyao; Ying, Tianlei; Zhang, Baohong; Lu, Jun (1 March 2022). "Nicotinamide mononucleotide (NMN) as an anti-aging health product – Promises and safety concerns". Journal of Advanced Research. 37: 267–278. doi:10.1016/j.jare.2021.08.003. hdl:10292/15010. ISSN 2090-1232. PMC 9039735. PMID 35499054. S2CID 238647478.
  8. ^ Stipp D (March 11, 2015). "Beyond Resveratrol: The Anti-Aging NAD Fad". Scientific American Blog Network.
  9. ^ Nadeeshani, Harshani; Li, Jinyao; Ying, Tianlei; Zhang, Baohong; Lu, Jun (2022-03-01). "Nicotinamide mononucleotide (NMN) as an anti-aging health product – Promises and safety concerns". Journal of Advanced Research. 37: 267–278. doi:10.1016/j.jare.2021.08.003. ISSN 2090-1232. PMC 9039735. PMID 35499054.
  10. ^ Irie, Junichiro; Inagaki, Emi; Fujita, Masataka; Nakaya, Hideaki; Mitsuishi, Masanori; Yamaguchi, Shintaro; Yamashita, Kazuya; Shigaki, Shuhei; Ono, Takashi; Yukioka, Hideo; Okano, Hideyuki (2020). "Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men". Endocrine Journal. 67 (2): 153–60. doi:10.1507/endocrj.EJ19-0313. ISSN 0918-8959. PMID 31685720.
  11. ^ Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, et al. (June 2021). "Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women". Science. 372 (6547): 1224–29. doi:10.1126/science.abe9985. PMC 8550608. PMID 33888596.
  12. ^ Liao, B; Zhao, Y; Wang, D; Zhang, X; Hao, X; Hu, M (2021). ""Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study"". Journal of the International Society of Sports Nutrition. 18 (1): 54. doi:10.1186/s12970-021-00442-4. PMC 8265078. PMID 34238308.
  13. ^ Yi Lin; et al. (Feb 2023). "The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial". Geroscience. 45 (1): 29–43. doi:10.1007/s11357-022-00705-1. PMC 9735188. PMID 36482258.
  14. ^ Cambronne XA, Kraus WL (October 2020). "+ Synthesis and Functions in Mammalian Cells". Trends in Biochemical Sciences. 45 (10): 858–73. doi:10.1016/j.tibs.2020.05.010. PMC 7502477. PMID 32595066.
  15. ^ Tarragó MG, Chini CC, Kanamori KS, Warner GM, Caride A, et al. (May 2018). "A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline". Cell Metab. 27 (5): 1081–95.e10. doi:10.1016/j.cmet.2018.03.016. PMC 5935140. PMID 29719225.
  16. ^ Mills, KF; Yoshida, S; Stein, LR; Grozio, A; Kubota, S; Sasaki, Y; Redpath, P; Migaud, ME; Apte, RS; Uchida, K; Yoshino, J; Imai, SI (13 December 2016). "Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice". Cell Metabolism. 24 (6): 795–806. doi:10.1016/j.cmet.2016.09.013. PMC 5668137. PMID 28068222.
  17. ^ Ryan, Finn (2016-12-06). "5 Anti-Aging Food Types You Should Already Be Eating". Bicycling. Retrieved 2022-01-20.
  18. ^ "Scientists identify new fuel-delivery route for cells". Washington University School of Medicine. 2019-01-07. Retrieved 2022-01-20.
  19. ^ nutraingredients-usa.com/Article/2023/02/16/Amazon-removing-NMN-dietary-supplements-citing-FDA-actions
  20. ^ a b "FDA Halts NMN Supplement Approval, Citing Pharmaceutical Potential".
  21. ^ a b Song Q, Zhou X, Xu K, Liu S, Zhu X, Yang J (November 2023). "The Safety and Antiaging Effects of Nicotinamide Mononucleotide in Human Clinical Trials: an Update". Adv Nutr. 14 (6): 1416–35. doi:10.1016/j.advnut.2023.08.008. PMC 10721522. PMID 37619764.
  22. ^ Figley, Matthew D.; Gu, Weixi; Nanson, Jeffrey D.; Shi, Yun; Sasaki, Yo; Cunnea, Katie; Malde, Alpeshkumar K.; Jia, Xinying; Luo, Zhenyao; Saikot, Forhad K.; Mosaiab, Tamim; Masic, Veronika; Holt, Stephanie; Hartley-Tassell, Lauren; McGuinness, Helen Y.; Manik, Mohammad K.; Bosanac, Todd; Landsberg, Michael J.; Kerry, Philip S.; Mobli, Mehdi; Hughes, Robert O.; Milbrandt, Jeffrey; Kobe, Bostjan; DiAntonio, Aaron; Ve, Thomas (7 April 2021). "SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration". Neuron. 109 (7): 1118–1136.e11. doi:10.1016/j.neuron.2021.02.009. PMC 8174188. PMID 33657413.
  23. ^ a b Di Stefano, M; Nascimento-Ferreira, I; Orsomando, G; Mori, V; Gilley, J; Brown, R; Janeckova, L; Vargas, M E; Worrell, L A; Loreto, A; Tickle, J; Patrick, J; Webster, J R M; Marangoni, M; Carpi, F M; Pucciarelli, S; Rossi, F; Meng, W; Sagasti, A; Ribchester, R R; Magni, G; Coleman, M P; Conforti, L (April 2015). "A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration". Cell Death and Differentiation. 22 (5): 731–742. doi:10.1038/cdd.2014.164. hdl:11581/387761. PMC 4392071. PMID 25323584.
  24. ^ Zhao, Zhi Ying; Xie, Xu Jie; Li, Wan Hua; Liu, Jun; Chen, Zhe; Zhang, Ben; Li, Ting; Li, Song Lu; Lu, Jun Gang; Zhang, Liangren; Zhang, Li-he; Xu, Zhengshuang; Lee, Hon Cheung; Zhao, Yong Juan (4 May 2019). "A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death". iScience. 15: 452–466. doi:10.1016/j.isci.2019.05.001. PMC 6531917. PMID 31128467.
  25. ^ Brazill, Jennifer M.; Li, Chong; Zhu, Yi; Zhai, R. Grace (26 April 2017). "NMNAT: It's an NAD+ Synthase… It's a Chaperone… It's a Neuroprotector". Current Opinion in Genetics & Development. 44: 156–162. doi:10.1016/j.gde.2017.03.014. PMC 5515290. PMID 28445802.
  26. ^ Gerdts, Josiah; Summers, Daniel W.; Milbrandt, Jeffrey; DiAntonio, Aaron (3 February 2016). "Axon self destruction: new links among SARM1, MAPKs, and NAD+ metabolism". Neuron. 89 (3): 449–460. doi:10.1016/j.neuron.2015.12.023. PMC 4742785. PMID 26844829.
  27. ^ Sasaki, Yo; Zhu, Jian; Shi, Yun; Gu, Weixi; Kobe, Bostjan; Ve, Thomas; DiAntonio, Aaron; Milbrandt, Jeffrey (November 2021). "Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection". Experimental Neurology. 345: 113842. doi:10.1016/j.expneurol.2021.113842. hdl:10072/407468. PMC 8571713. PMID 34403688.
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