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 NAMPTgene.[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 neutrophilapoptosis.
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 21young (under36) and 22old (over54) 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
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
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
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 pancreaticbeta cells and brain neurons.[27]
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.[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
NAMPT has increasingly been researched as a potential drug target, with activators of NAMPT having potential applications as anti-aging drugs, while inhibitors of NAMPT may be useful for the treatment of certain forms of cancer.[33][34][35][36][37][38][39]
Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, iNAMPT is often amplified in cancer cells.[40][41] APO866 (FK866) is an experimental drug that inhibits this enzyme. It was tested for treatment of advanced melanoma, cutaneous T-cell lymphoma (CTL), and refractory or relapsed B-chronic lymphocytic leukemia., but was dropped from development due to disappointing efficacy results in trials.[42] However, it has been shown to inhibit epithelial–mesenchymal transition (EMT) and inhibit tumor-associated angiogenesis,[9] and may be useful for other medical indications.
Anti-aging biomedical company Calico has licensed the experimental P7C3 analogs involved in enhancing iNAMPT activity.[43] P7C3 compounds have been shown in a number of publications to be beneficial in animal models for age-related neurodegeneration.[44][45]
12Revollo 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. PMID17268245. S2CID31308112.
↑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. PMID28756747. S2CID196644501.
↑Cameron AM, Castoldi A, Sanin DE, Flachsmann LJ, Field CS, Puleston DJ, etal. (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. PMID30858618. S2CID73728924.
↑Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, etal. (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. PMID16901503.
↑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. PMID16783377. S2CID13305867.
↑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. PMID16531748. S2CID46178743.
↑Kozako T, Aikawa A, Ohsugi T, Uchida YI, Kato N, Sato K, etal. (2019). "High expression of NAMPT in adult T-cell leukemia/Lymphoma and anti-tumor activity of a NAMPT inhibitor". European Journal of Pharmacology. 865 172738. doi:10.1016/j.ejphar.2019.172738. PMID31614144.
↑Yao H, Liu M, Wang L, Zu Y, Wu C, Li C, etal. (2022). "Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity". Cell Research. 32 (6): 570–584. doi:10.1038/s41422-022-00651-9. PMID35459935.
↑Manickam R, Santhana S, Xuan W, Bisht KS, Tipparaju SM (2025). "Nampt: A new therapeutic target for modulating NAD+ levels in metabolic, cardiovascular, and neurodegenerative diseases". Canadian Journal of Physiology and Pharmacology. 103 (7): 208–224. Bibcode:2025CJPP..103.0400M. doi:10.1139/cjpp-2024-0400. PMID40203459.
↑Pinkerton AB, Sessions EH, Hershberger P, Maloney PR, Peddibhotla S, Hopf M, Sergienko E, Ma CT, Smith LH, Jackson MR, Tanaka J, Tsuji T, Akiu M, Cohen SE, Nakamura T, Gardell SJ. Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators. Bioorg Med Chem Lett. 2021 Jun 1;41:128007. doi:10.1016/j.bmcl.2021.128007PMID33798699
↑Akiu M, Tsuji T, Sogawa Y, Terayama K, Yokoyama M, Tanaka J, Asano D, Sakurai K, Sergienko E, Sessions EH, Gardell SJ, Pinkerton AB, Nakamura T. Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition. Bioorg Med Chem Lett. 2021 Jul 1;43:128048. doi:10.1016/j.bmcl.2021.128048PMID33887438
↑Wang L, Liu M, Zu Y, Yao H, Wu C, Zhang R, Ma W, Lu H, Xi S, Liu Y, Hua L, Wang G, Tang Y. Optimization of NAMPT activators to achieve in vivo neuroprotective efficacy. Eur J Med Chem. 2022 Jun 5;236:114260. doi:10.1016/j.ejmech.2022.114260PMID35385807
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. PMID16531748. S2CID46178743.
Bełtowski J (June 2006). "Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity?". Medical Science Monitor. 12 (6): RA112 –RA119. PMID16733497.
Pilz S, Mangge H, Obermayer-Pietsch B, März W (February 2007). "Visfatin/pre-B-cell colony-enhancing factor: a protein with various suggested functions". Journal of Endocrinological Investigation. 30 (2): 138–144. doi:10.1007/bf03347412. PMID17392604. S2CID20329604.
Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (October 1990). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes". DNA and Cell Biology. 9 (8): 579–587. doi:10.1089/dna.1990.9.579. PMID1702972.
Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, etal. (January 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID15592455. S2CID7200157.
2g96: Crystal Structure of Visfatin/Pre-B Cell Colony Enhancing Factor 1/Nicotinamide Phosphoribosyltransferase In Complex with Nicotinamide Mononucleotide
2g97: Crystal Structure of Visfatin/Pre-B Cell Colony Enhancing Factor 1/Nicotinamide Phosphoribosyltransferase In Complex with the Specific Inhibitor FK-866
2gvg: Crystal Structure of human NMPRTase and its complex with NMN
2gvj: Crystal Structure of Human NMPRTase in complex with FK866
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