Nicotinamide phosphoribosyltransferase

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NAMPT
Protein PBEF1 PDB 2g95.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNAMPT, 1110035O14Rik, PBEF, PBEF1, VF, VISFATIN, nicotinamide phosphoribosyltransferase
External IDsOMIM: 608764 MGI: 1929865 HomoloGene: 4201 GeneCards: NAMPT
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005746
NM_182790

NM_021524

RefSeq (protein)

NP_005737

NP_067499

Location (UCSC)Chr 7: 106.25 – 106.29 MbChr 12: 32.82 – 32.85 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

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.

Reaction[edit]

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[edit]

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]

Function[edit]

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+).[15] 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.[15] De novo synthesis of NAD+ from tryptophan occurs only in the liver and kidney, overwhelmingly in the liver.[15]

Nomenclature[edit]

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[edit]

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.[16] 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.[17]

eNAMPT can exist as a dimer or as a monomer, but is normally a circulating dimer.[16] As a monomer, eNAMPT has pro-inflammatory effects that are independent of NAD+, whereas the dimeric form of eNAMPT protects against these effects.[16]

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.[18] Rongvaux et al.[19] demonstrated genetically that the mouse PBEF gene conferred Nampt enzymatic activity and NAD-independent growth to bacteria lacking nadV. Revollo et al.[20] determined biochemically that the mouse PBEF gene product encodes an eNAMPT enzyme, capable of modulating intracellular NAD levels. Others have since confirmed these findings.[21] 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.[22][23][24]

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.[25]

Hormone claim retracted[edit]

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.[26] In particular, Nampt/PBEF was recently re-identified as a "new visceral fat-derived hormone" named visfatin.[27] 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.[27] 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.[27] 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.[27][28][29] 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,[27] who first described Visfatin as a visceral-fat derived hormone that acts by binding and activating the insulin receptor, retracted the entire paper[27] 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.[30]

As a drug target[edit]

Because cancer cells utilize increased glycolysis, and because NAD enhances glycolysis, iNAMPT is often amplified in cancer cells.[31][32] APO866 is an experimental drug that inhibits this enzyme.[33] 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.[34] P7C3 compounds have been shown in a number of publications to be beneficial in animal models for age-related neurodegeneration.[35][36]

References[edit]

  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 (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): 1431–7. 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): 164–70. doi:10.1097/MOG.0b013e32801b3c8f. PMID 17268245. S2CID 31308112.
  8. ^ a b Galli U, Colombo G, Travelli C, 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.
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  23. ^ Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, Lee YS, Kim JB, Kim KK, Suh SW, Eom SH (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.
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  25. ^ Imai S (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.
  26. ^ Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD, Marshall JC (May 2004). "Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis". The Journal of Clinical Investigation. 113 (9): 1318–27. doi:10.1172/JCI19930. PMC 398427. PMID 15124023.
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  30. ^ 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 (October 2007). "Retraction". Science. 318 (5850): 565.2–565. doi:10.1126/science.318.5850.565b. PMID 17962537. S2CID 220091956.
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  33. ^ APO866 Not Effective for Cutaneous T-Cell Lymphoma. March 2016
  34. ^ "UT Southwestern researchers discover novel class of NAMPT activators for neurodegenerative disease; Calico enters into exclusive collaboration with 2M to develop UTSW technology".
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Further reading[edit]

External links[edit]