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Nicotinamide phosphoribosyltransferase

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Nicotinamide phosphoribosyltransferase (NAmPRTase or NAMPT), formerly known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin for its extracellular form (eNAMPT),[5] is an enzyme that in humans is encoded by the NAMPT gene.[6] 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.[7] iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present.[8] eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4,[9] that promotes B cell maturation, and that inhibits neutrophil apoptosis.

NAMPT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNAMPT, 1110035O14Rik, PBEF, PBEF1, VF, VISFATIN, nicotinamide phosphoribosyltransferase
External IDsOMIM: 608764; MGI: 1929865; HomoloGene: 4201; GeneCards: NAMPT; OMA:NAMPT - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10135

59027

Ensembl

ENSG00000105835

ENSMUSG00000020572

UniProt

P43490

Q99KQ4

RefSeq (mRNA)

NM_005746
NM_182790

NM_021524

RefSeq (protein)

NP_005737

NP_067499

Location (UCSC)Chr 7: 106.25 – 106.29 MbChr 12: 32.87 – 32.9 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
nicotinamide phosphoribosyltransferase
Identifiers
EC no.2.4.2.12
CAS no.9030-27-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

Reaction

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iNAMPT catalyzes the following chemical reaction:

nicotinamide + 5-phosphoribosyl-1-pyrophosphate (PRPP)   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.[7]

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

Expression and regulation

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The liver has the highest iNAMPT activity of any organ, about 10-20 times greater activity than kidney, spleen, heart, muscle, brain or lung.[10] 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.[11]

Endurance-trained athletes have twice the expression of iNAMPT in skeletal muscle compared with sedentary type 2 diabetic persons.[12] In a six-week study comparing legs trained by endurance exercise with untrained legs, iNAMPT was increased in the endurance-trained legs.[12] 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).[13]

Aging, obesity, and chronic inflammation all reduce iNAMPT (and consequently NAD+) in multiple tissues,[14] and NAMPT activity was shown to promote a proinflammatory transcriptional reprogramming of immune cells (e.g. macrophages[15]) and brain-resident astrocytes.[16]

Function

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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+).[17] 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.[17] De novo synthesis of NAD+ from tryptophan occurs only in the liver and kidney, overwhelmingly in the liver.[17]

Nomenclature

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

  • NMN pyrophosphorylase,
  • nicotinamide mononucleotide pyrophosphorylase,
  • nicotinamide mononucleotide synthetase, and
  • NMN synthetase.

Extracellular NAMPT

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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).[5] 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.[18] eNAMPT may act more as a cytokine, although its receptor (possibly TLR4) has not been proven.[8] It has been demonstrated that eNAMPT could bind to and activate TLR4.[19]

eNAMPT can exist as a dimer or as a monomer, but is normally a circulating dimer.[18] As a monomer, eNAMPT has pro-inflammatory effects that are independent of NAD+, whereas the dimeric form of eNAMPT protects against these effects.[18]

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).[6] 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.[20] Rongvaux et al.[21] demonstrated genetically that the mouse PBEF gene conferred Nampt enzymatic activity and NAD-independent growth to bacteria lacking nadV. Revollo et al.[22] determined biochemically that the mouse PBEF gene product encodes an eNAMPT enzyme, capable of modulating intracellular NAD levels. Others have since confirmed these findings.[23] 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.[24][25][26]

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.[27]

Hormone claim retracted

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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.[28] In particular, Nampt/PBEF was recently re-identified as a "new visceral fat-derived hormone" named visfatin.[29] 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.[29] 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.[29] 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.[29][30][31] 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,[29] who first described Visfatin as a visceral-fat derived hormone that acts by binding and activating the insulin receptor, retracted the entire paper[29] 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.[32]

As a drug target

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Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, iNAMPT is often amplified in cancer cells.[33][34] APO866 is an experimental drug that inhibits this enzyme.[35] 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.[9]

Anti-aging biomedical company Calico has licensed the experimental P7C3 analogs involved in enhancing iNAMPT activity.[36] P7C3 compounds have been shown in a number of publications to be beneficial in animal models for age-related neurodegeneration.[37][38]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105835 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020572 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Grolla AA, Travelli C, Genazzani AA, Sethi JK (July 2016). "Extracellular nicotinamide phosphoribosyltransferase, a new cancer metabokine". British Journal of Pharmacology. 173 (14): 2182–2194. doi:10.1111/bph.13505. PMC 4919578. PMID 27128025.
  6. ^ a b Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I (February 1994). "Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor". Molecular and Cellular Biology. 14 (2): 1431–1437. doi:10.1128/MCB.14.2.1431. PMC 358498. PMID 8289818.
  7. ^ a b Revollo JR, Grimm AA, Imai S (March 2007). "The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals". Current Opinion in Gastroenterology. 23 (2): 164–170. doi:10.1097/MOG.0b013e32801b3c8f. PMID 17268245. S2CID 31308112.
  8. ^ a b Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA (2020). "Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy". Frontiers in Pharmacology. 11: 656. doi:10.3389/fphar.2020.00656. PMC 7235340. PMID 32477131.
  9. ^ a b Galli U, Colombo G, Travelli C, Tron GC, Genazzani AA, Grolla AA (2020). "Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy". Frontiers in Pharmacology. 11: 656. doi:10.3389/fphar.2020.00656. PMC 7235340. PMID 32477131.
  10. ^ Hwang ES, Song SB (September 2017). "Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells". Cellular and Molecular Life Sciences. 74 (18): 3347–3362. doi:10.1007/s00018-017-2527-8. PMC 11107671. PMID 28417163. S2CID 25896400.
  11. ^ Choi SE, Fu T, Seok S, Kim DH, Yu E, Lee KW, et al. (December 2013). "Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT". Aging Cell. 12 (6): 1062–1072. doi:10.1111/acel.12135. PMC 3838500. PMID 23834033.
  12. ^ a b Jadeja RN, Thounaojam MC, Bartoli M, Martin PM (2020). "Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration". Oxidative Medicine and Cellular Longevity. 2020: 2692794. doi:10.1155/2020/2692794. PMC 7238357. PMID 32454935.
  13. ^ de Guia RM, Agerholm M, Nielsen TS, Consitt LA, Søgaard D, Helge JW, et al. (July 2019). "Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle". Physiological Reports. 7 (12): e14139. doi:10.14814/phy2.14139. PMC 6577427. PMID 31207144.
  14. ^ Poljsak B (June 2018). "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. doi:10.1089/rej.2017.1975. PMID 28756747. S2CID 196644501.
  15. ^ Cameron AM, Castoldi A, Sanin DE, Flachsmann LJ, Field CS, Puleston DJ, et al. (April 2019). "Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species-mediated DNA damage". Nature Immunology. 20 (4): 420–432. doi:10.1038/s41590-019-0336-y. PMID 30858618. S2CID 73728924.
  16. ^ Meyer T, Shimon D, Youssef S, Yankovitz G, Tessler A, Chernobylsky T, et al. (August 2022). "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. Bibcode:2022PNAS..11911310M. doi:10.1073/pnas.2211310119. PMC 9436380. PMID 35994674.
  17. ^ a b c Liu L, Su X, Quinn WJ, Hui S, Krukenberg K, Frederick DW, et al. (May 2018). "Quantitative Analysis of NAD Synthesis-Breakdown Fluxes". Cell Metabolism. 27 (5): 1067–1080.e5. doi:10.1016/j.cmet.2018.03.018. PMC 5932087. PMID 29685734.
  18. ^ a b c Yoshino J, Baur JA, Imai SI (March 2018). "NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR". Cell Metabolism. 27 (3): 513–528. doi:10.1016/j.cmet.2017.11.002. PMC 5842119. PMID 29249689.
  19. ^ Camp SM, Ceco E, Evenoski CL, Danilov SM, Zhou T, Chiang ET, et al. (August 2015). "Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury". Scientific Reports. 5: 13135. Bibcode:2015NatSR...513135C. doi:10.1038/srep13135. PMC 4536637. PMID 26272519.
  20. ^ Martin PR, Shea RJ, Mulks MH (February 2001). "Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence". Journal of Bacteriology. 183 (4): 1168–1174. doi:10.1128/JB.183.4.1168-1174.2001. PMC 94989. PMID 11157928.
  21. ^ Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, et al. (November 2002). "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. doi:10.1002/1521-4141(200211)32:11<3225::AID-IMMU3225>3.0.CO;2-L. PMID 12555668. S2CID 11043568.
  22. ^ Revollo JR, Grimm AA, Imai S (December 2004). "The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells". The Journal of Biological Chemistry. 279 (49): 50754–50763. doi:10.1074/jbc.M408388200. PMID 15381699.
  23. ^ van der Veer E, Nong Z, O'Neil C, Urquhart B, Freeman D, Pickering JG (July 2005). "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. doi:10.1161/01.RES.0000173298.38808.27. PMID 15947248.
  24. ^ Wang T, Zhang X, Bheda P, Revollo JR, Imai S, Wolberger C (July 2006). "Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme". Nature Structural & Molecular Biology. 13 (7): 661–662. doi:10.1038/nsmb1114. PMID 16783373. S2CID 28674013.
  25. ^ Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, et al. (September 2006). "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. doi:10.1016/j.jmb.2006.06.082. PMID 16901503.
  26. ^ Khan JA, Tao X, Tong L (July 2006). "Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents". Nature Structural & Molecular Biology. 13 (7): 582–588. doi:10.1038/nsmb1105. PMID 16783377. S2CID 13305867.
  27. ^ Imai SI (2016). "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. doi:10.1038/npjsba.2016.18. PMC 5516857. PMID 28725474.
  28. ^ Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD, et al. (May 2004). "Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis". The Journal of Clinical Investigation. 113 (9): 1318–1327. doi:10.1172/JCI19930. PMC 398427. PMID 15124023.
  29. ^ a b c d e f Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al. (January 2005). "Visfatin: a protein secreted by visceral fat that mimics the effects of insulin". Science. 307 (5708): 426–430. Bibcode:2005Sci...307..426F. doi:10.1126/science.1097243. PMID 15604363. S2CID 86231101. (Retracted, see doi:10.1126/science.318.5850.565b, PMID 17962537,  Retraction Watch)
  30. ^ Stephens JM, Vidal-Puig AJ (April 2006). "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. doi:10.1097/01.mol.0000217893.77746.4b. PMID 16531748. S2CID 46178743.
  31. ^ Arner P (January 2006). "Visfatin--a true or false trail to type 2 diabetes mellitus". The Journal of Clinical Endocrinology and Metabolism. 91 (1): 28–30. doi:10.1210/jc.2005-2391. PMID 16401830.
  32. ^ Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al. (October 2007). "Retraction". Science. 318 (5850): 565. doi:10.1126/science.318.5850.565b. PMID 17962537. S2CID 220091956.
  33. ^ Yaku K, Okabe K, Hikosaka K, Nakagawa T (2018). "NAD Metabolism in Cancer Therapeutics". Frontiers in Oncology. 8: 622. doi:10.3389/fonc.2018.00622. PMC 6315198. PMID 30631755.
  34. ^ Pramono AA, Rather GM, Herman H, Lestari K, Bertino JR (February 2020). "NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview". Biomolecules. 10 (3): 358. doi:10.3390/biom10030358. PMC 7175141. PMID 32111066.
  35. ^ APO866 Not Effective for Cutaneous T-Cell Lymphoma. March 2016
  36. ^ "UT Southwestern researchers discover novel class of NAMPT activators for neurodegenerative disease; Calico enters into exclusive collaboration with 2M to develop UTSW technology" (Press release).
  37. ^ Cain C (2014). "NAMPT neuroprotection". Science-Business EXchange. 7 (38): 1112. doi:10.1038/scibx.2014.1112.
  38. ^ Wang G, Han T, Nijhawan D, Theodoropoulos P, Naidoo J, Yadavalli S, et al. (September 2014). "P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage". Cell. 158 (6): 1324–1334. doi:10.1016/j.cell.2014.07.040. PMC 4163014. PMID 25215490.

Further reading

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