Nicotinamide phosphoribosyltransferase explained

nicotinamide phosphoribosyltransferase
Ec Number:2.4.2.12
Cas Number:9030-27-7
Go Code:0047280

Nicotinamide phosphoribosyltransferase (NAmPRTase or NAMPT), 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.[1] 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.[2] iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present.[3] eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4,[4] that promotes B cell maturation, and that inhibits neutrophil apoptosis.

Reaction

iNAMPT catalyzes the following chemical reaction:

nicotinamide + 5-phosphoribosyl-1-pyrophosphate (PRPP)

\rightleftharpoons

nicotinamide mononucleotide (NMN) + pyrophosphate (PPi)

Thus, the two substrates of this enzyme are nicotinamide and 5-phosphoribosyl-1-pyrophosphate (PRRP), whereas its two products are nicotinamide mononucleotide and pyrophosphate.[2]

This enzyme belongs to the family of glycosyltransferases, to be specific, the pentosyltransferases. This enzyme participates in nicotinate and nicotinamide metabolism.

Expression and regulation

The liver has the highest iNAMPT activity of any organ, about 10-20 times greater activity than kidney, spleen, heart, muscle, brain or lung.[5] iNAMPT is downregulated by an increase of miR-34a in obesity via a 3'UTR functional binding site of iNAMPT mRNA resulting in a reduction of NAD(+) and decreased SIRT1 activity.[6]

Endurance-trained athletes have twice the expression of iNAMPT in skeletal muscle compared with sedentary type 2 diabetic persons.[7] In a six-week study comparing legs trained by endurance exercise with untrained legs, iNAMPT was increased in the endurance-trained legs. A study of 21 young (under 36) and 22 old (over 54) adults subject to 12 weeks of aerobic and resistance exercise showed aerobic exercise to increase skeletal muscle iNAMPT 12% and 28% in young and old (respectively) and resistance exercise to increase skeletal muscle iNAMPT 25% and 30% in young and old (respectively).[8]

Aging, obesity, and chronic inflammation all reduce iNAMPT (and consequently NAD+) in multiple tissues,[9] and NAMPT activity was shown to promote a proinflammatory transcriptional reprogramming of immune cells (e.g. macrophages[10]) and brain-resident astrocytes.[11]

Function

iNAMPT catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide (NMN), the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD+).[12] This salvage pathway, reusing NAM from enzymes using NAD+ (sirtuins, PARPs, CD38) and producing NAM as a waste product, is the major source of NAD+ production in the body. De novo synthesis of NAD+ from tryptophan occurs only in the liver and kidney, overwhelmingly in the liver.

Nomenclature

The systematic name of this enzyme class is nicotinamide-nucleotide:diphosphate phospho-alpha-D-ribosyltransferase. Other names in common use include:

Extracellular NAMPT

Extracellular NAMPT (eNAMPT) is functionally different from intracellular NAMPT (iNAMPT), and less well understood (which is why the enzyme has been given so many names: NAMPT, PBEF and visfatin).[13] iNAMPT is secreted by many cell types (nobably adipocytes) to become eNAMPT. The sirtuin 1 (SIRT1) enzyme is required for eNAMPT secretion from adipose tissue. eNAMPT may act more as a cytokine, although its receptor (possibly TLR4) has not been proven. It has been demonstrated that eNAMPT could bind to and activate TLR4.[14]

eNAMPT can exist as a dimer or as a monomer, but is normally a circulating dimer.[15] As a monomer, eNAMPT has pro-inflammatory effects that are independent of NAD+, whereas the dimeric form of eNAMPT protects against these effects.

eNAMPT/PBEF/visfatin was originally cloned as a putative cytokine shown to enhance the maturation of B cell precursors in the presence of Interleukin-7 (IL-7) and stem cell factor, it was therefore named "pre-B cell colony-enhancing factor" (PBEF).[1] When the gene encoding the bacterial nicotinamide phosphoribosyltransferase (nadV) was first isolated in Haemophilus ducreyi, it was found to exhibit significant homology to the mammalian PBEF gene.[16] Rongvaux et al.[17] demonstrated genetically that the mouse PBEF gene conferred Nampt enzymatic activity and NAD-independent growth to bacteria lacking nadV. Revollo et al.[18] determined biochemically that the mouse PBEF gene product encodes an eNAMPT enzyme, capable of modulating intracellular NAD levels. Others have since confirmed these findings.[19] More recently, several groups have reported the crystal structure of Nampt/PBEF/visfatin and they all show that this protein is a dimeric type II phosphoribosyltransferase enzyme involved in NAD biosynthesis.[20] [21] [22]

eNAMPT has been shown to be more enzymatically active than iNAMPT, supporting the proposal that eNAMPT from adipose tissue enhances NAD+ in tissues with low levels of iNAMPT, notably pancreatic beta cells and brain neurons.[23]

Hormone claim retracted

Although the original cytokine function of PBEF has not been confirmed to date, others have since reported or suggested a cytokine-like function for this protein.[24] In particular, Nampt/PBEF was recently re-identified as a "new visceral fat-derived hormone" named visfatin.[25] It is reported that visfatin is enriched in the visceral fat of both humans and mice and that its plasma levels increase during the development of obesity.[25] Noteworthy is that visfatin is reported to exert insulin-mimetic effects in cultured cells and to lower plasma glucose levels in mice by binding to and activating the insulin receptor.[25] However, the physiological relevance of visfatin is still in question because its plasma concentration is 40 to 100-fold lower than that of insulin despite having similar receptor-binding affinity.[25] [26] [27] In addition, the ability of visfatin to bind and activate the insulin-receptor has yet to be confirmed by other groups.

On 26 October 2007, A. Fukuhara (first author), I.Shimomura (senior author) and the other co-authors of the paper,[25] who first described Visfatin as a visceral-fat derived hormone that acts by binding and activating the insulin receptor, retracted the entire paper[25] at the suggestion of the editor of the journal 'Science' and recommendation of the Faculty Council of Osaka University Medical School after a report of the Committee for Research Integrity.[28]

As a drug target

Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, iNAMPT is often amplified in cancer cells.[29] [30] APO866 is an experimental drug that inhibits this enzyme.[31] It is being tested for treatment of advanced melanoma, cutaneous T-cell lymphoma (CTL), and refractory or relapsed B-chronic lymphocytic leukemia.

The NAMPT inhibitor FK866 has been shown to inhibit epithelial–mesenchymal transition (EMT), and may also inhibit tumor-associated angiogenesis.

Anti-aging biomedical company Calico has licensed the experimental P7C3 analogs involved in enhancing iNAMPT activity.[32] P7C3 compounds have been shown in a number of publications to be beneficial in animal models for age-related neurodegeneration.[33] [34]

Further reading

Notes and References

  1. Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I . Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor . Molecular and Cellular Biology . 14 . 2 . 1431–1437 . February 1994 . 8289818 . 358498 . 10.1128/MCB.14.2.1431 .
  2. Revollo JR, Grimm AA, Imai S . The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals . Current Opinion in Gastroenterology . 23 . 2 . 164–170 . March 2007 . 17268245 . 10.1097/MOG.0b013e32801b3c8f . 31308112 .
  3. Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA . Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy . Frontiers in Pharmacology . 11 . 656 . 2020 . 32477131 . 7235340 . 10.3389/fphar.2020.00656 . free .
  4. Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA . Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy . Frontiers in Pharmacology . 11 . 656 . 2020 . 32477131 . 7235340 . 10.3389/fphar.2020.00656 . free .
  5. Hwang ES, Song SB . Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells . Cellular and Molecular Life Sciences . 74 . 18 . 3347–3362 . September 2017 . 28417163 . 10.1007/s00018-017-2527-8 . 25896400 . 11107671 .
  6. Choi SE, Fu T, Seok S, Kim DH, Yu E, Lee KW, Kang Y, Li X, Kemper B, Kemper JK . Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT . Aging Cell . 12 . 6 . 1062–1072 . December 2013 . 23834033 . 3838500 . 10.1111/acel.12135 .
  7. Jadeja RN, Thounaojam MC, Bartoli M, Martin PM . Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration . Oxidative Medicine and Cellular Longevity . 2020 . 2692794 . 2020 . 32454935 . 7238357 . 10.1155/2020/2692794 . free .
  8. de Guia RM, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, Larsen S, Brandauer J, Houmard JA, Treebak JT . Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle . Physiological Reports . 7 . 12 . e14139 . July 2019 . 31207144 . 6577427 . 10.14814/phy2.14139 .
  9. Poljsak B . NAMPT-Mediated NAD Biosynthesis as the Internal Timing Mechanism: In NAD+ World, Time Is Running in Its Own Way . Rejuvenation Research . 21 . 3 . 210–224 . June 2018 . 28756747 . 10.1089/rej.2017.1975 . 196644501 .
  10. Cameron AM, Castoldi A, Sanin DE, Flachsmann LJ, Field CS, Puleston DJ, Kyle RL, Patterson AE, Hässler F, Buescher JM, Kelly B, Pearce EL, Pearce EJ . Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species-mediated DNA damage . Nature Immunology . 20 . 4 . 420–432 . April 2019 . 30858618 . 10.1038/s41590-019-0336-y . 73728924 .
  11. Meyer T, Shimon D, Youssef S, Yankovitz G, Tessler A, Chernobylsky T, Gaoni-Yogev A, Perelroizen R, Budick-Harmelin N, Steinman L, Mayo L . NAD+ metabolism drives astrocyte proinflammatory reprogramming in central nervous system autoimmunity . Proceedings of the National Academy of Sciences of the United States of America . 119 . 35 . e2211310119 . August 2022 . 35994674 . 9436380 . 10.1073/pnas.2211310119 . free . 2022PNAS..11911310M .
  12. Liu L, Su X, Quinn WJ, Hui S, Krukenberg K, Frederick DW, Redpath P, Zhan L, Chellappa K, White E, Migaud M, Mitchison TJ, Baur JA, Rabinowitz JD . Quantitative Analysis of NAD Synthesis-Breakdown Fluxes . Cell Metabolism . 27 . 5 . 1067–1080.e5 . May 2018 . 29685734 . 5932087 . 10.1016/j.cmet.2018.03.018 .
  13. Grolla AA, Travelli C, Genazzani AA, Sethi JK . Extracellular nicotinamide phosphoribosyltransferase, a new cancer metabokine . British Journal of Pharmacology . 173 . 14 . 2182–2194 . July 2016 . 27128025 . 4919578 . 10.1111/bph.13505 .
  14. Camp SM, Ceco E, Evenoski CL, Danilov SM, Zhou T, Chiang ET, Moreno-Vinasco L, Mapes B, Zhao J, Gursoy G, Brown ME, Adyshev DM, Siddiqui SS, Quijada H, Sammani S, Letsiou E, Saadat L, Yousef M, Wang T, Liang J, Garcia JG . Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury . Scientific Reports . 5 . 13135 . August 2015 . 26272519 . 4536637 . 10.1038/srep13135 . 2015NatSR...513135C .
  15. Yoshino J, Baur JA, Imai SI . NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR . Cell Metabolism . 27 . 3 . 513–528 . March 2018 . 29249689 . 5842119 . 10.1016/j.cmet.2017.11.002 .
  16. Martin PR, Shea RJ, Mulks MH . Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence . Journal of Bacteriology . 183 . 4 . 1168–1174 . February 2001 . 11157928 . 94989 . 10.1128/JB.183.4.1168-1174.2001 .
  17. Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F . Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis . European Journal of Immunology . 32 . 11 . 3225–3234 . November 2002 . 12555668 . 10.1002/1521-4141(200211)32:11<3225::AID-IMMU3225>3.0.CO;2-L . 11043568 . free .
  18. Revollo JR, Grimm AA, Imai S . The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells . The Journal of Biological Chemistry . 279 . 49 . 50754–50763 . December 2004 . 15381699 . 10.1074/jbc.M408388200 . free .
  19. van der Veer E, Nong Z, O'Neil C, Urquhart B, Freeman D, Pickering JG . Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation . Circulation Research . 97 . 1 . 25–34 . July 2005 . 15947248 . 10.1161/01.RES.0000173298.38808.27 . free .
  20. Wang T, Zhang X, Bheda P, Revollo JR, Imai S, Wolberger C . Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme . Nature Structural & Molecular Biology . 13 . 7 . 661–662 . July 2006 . 16783373 . 10.1038/nsmb1114 . 28674013 .
  21. Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, Lee YS, Kim JB, Kim KK, Suh SW, Eom SH . Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866 . Journal of Molecular Biology . 362 . 1 . 66–77 . September 2006 . 16901503 . 10.1016/j.jmb.2006.06.082 .
  22. Khan JA, Tao X, Tong L . Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents . Nature Structural & Molecular Biology . 13 . 7 . 582–588 . July 2006 . 16783377 . 10.1038/nsmb1105 . 13305867 .
  23. Imai SI . The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control . npj Systems Biology and Applications . 2 . 16018 . 2016 . 28725474 . 5516857 . 10.1038/npjsba.2016.18 .
  24. Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD, Marshall JC . Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis . The Journal of Clinical Investigation . 113 . 9 . 1318–1327 . May 2004 . 15124023 . 398427 . 10.1172/JCI19930 .
  25. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I . Visfatin: a protein secreted by visceral fat that mimics the effects of insulin . Science . 307 . 5708 . 426–430 . January 2005 . 15604363 . 10.1126/science.1097243 . 86231101 . 2005Sci...307..426F . free .
  26. Stephens JM, Vidal-Puig AJ . An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity . Current Opinion in Lipidology . 17 . 2 . 128–131 . April 2006 . 16531748 . 10.1097/01.mol.0000217893.77746.4b . 46178743 .
  27. Arner P . Visfatin--a true or false trail to type 2 diabetes mellitus . The Journal of Clinical Endocrinology and Metabolism . 91 . 1 . 28–30 . January 2006 . 16401830 . 10.1210/jc.2005-2391 . free .
  28. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I . Retraction . Science . 318 . 5850 . 565 . October 2007 . 17962537 . 10.1126/science.318.5850.565b . 220091956 .
  29. Yaku K, Okabe K, Hikosaka K, Nakagawa T . NAD Metabolism in Cancer Therapeutics . Frontiers in Oncology . 8 . 622 . 2018 . 30631755 . 6315198 . 10.3389/fonc.2018.00622 . free .
  30. Pramono AA, Rather GM, Herman H, Lestari K, Bertino JR . NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview . Biomolecules . 10 . 3 . 358 . February 2020 . 32111066 . 7175141 . 10.3390/biom10030358 . free .
  31. http://www.cancernetwork.com/news/apo866-not-effective-cutaneous-t-cell-lymphoma APO866 Not Effective for Cutaneous T-Cell Lymphoma. March 2016
  32. UT Southwestern researchers discover novel class of NAMPT activators for neurodegenerative disease; Calico enters into exclusive collaboration with 2M to develop UTSW technology.
  33. NAMPT neuroprotection. Science-Business EXchange. 7. 38. 1112. 10.1038/scibx.2014.1112. 2014. Cain C .
  34. Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J, Yadavalli S, Mirzaei H, Pieper AA, Ready JM, McKnight SL . P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage . Cell . 158 . 6 . 1324–1334 . September 2014 . 25215490 . 4163014 . 10.1016/j.cell.2014.07.040 .

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