Nicotinamide phosphoribosyltransferase

Nicotinamide phosphoribosyltransferase
PDB rendering based on 2g95.
Available structures PDB 2E5B, 2E5C, 2E5D, 2GVG, 2GVJ, 3DGR, 3DHD, 3DHF, 3DKJ, 3DKL
Identifiers
Symbols	NAMPT; 1110035O14Rik; DKFZp666B131; MGC117256; PBEF; PBEF1; VF; VISFATIN
External IDs	OMIM: 608764 MGI: 1929865 HomoloGene: 4201 GeneCards: NAMPT Gene
EC number	2.4.2.12
Gene Ontology Molecular function • nicotinate-nucleotide diphosphorylase (carboxylating) activity • nicotinate phosphoribosyltransferase activity • cytokine activity • transferase activity, transferring glycosyl groups • nicotinamide phosphoribosyltransferase activity Cellular component • cytoplasm • cytosol Biological process • vitamin metabolic process • water-soluble vitamin metabolic process • nicotinamide metabolic process • signal transduction • cell-cell signaling • positive regulation of cell proliferation • insulin receptor signaling pathway • NAD biosynthetic process • pyridine nucleotide biosynthetic process • NAD metabolic process • positive regulation of nitric-oxide synthase biosynthetic process • adipose tissue development Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10135	59027
Ensembl	ENSG00000105835	ENSMUSG00000020572
UniProt	P43490	Q3TLX1
RefSeq (mRNA)	NM_005746.2	NM_021524.2
RefSeq (protein)	NP_005737.1	NP_067499.2
Location (UCSC)	Chr 7: 105.89 – 105.93 Mb	Chr 12: 33.51 – 33.54 Mb
PubMed search	[1]	[2]

nicotinamide phosphoribosyltransferase
Identifiers
EC number	2.4.2.12
CAS number	9030-27-7
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles

Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) also known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin is an enzyme that in humans is encoded by the PBEF1 gene.^[1] This protein has also been reported to be a cytokine (PBEF) that promotes B cell maturation and inhibits neutrophil apoptosis.

Reaction

NAmPRTase catalyzes the following chemical reaction:

nicotinamide D-ribonucleotide + diphosphate $\rightleftharpoons$ nicotinamide + 5-phospho-alpha-D-ribose 1-diphosphate

Thus, the two substrates of this enzyme are nicotinamide D-ribonucleotide and diphosphate, whereas its two products are nicotinamide and 5-phospho-alpha-D-ribose 1-diphosphate.

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

Function

NAmPRTase catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, one step in the biosynthesis of nicotinamide adenine dinucleotide. The protein is an adipokine that is localized to the bloodstream and has various functions, including the promotion of vascular smooth muscle cell maturation and inhibition of neutrophil apoptosis. It also activates insulin receptor and has insulin-mimetic effects, lowering blood glucose and improving insulin sensitivity. The protein is highly expressed in visceral fat and serum levels of the protein correlate with obesity. This gene has a pseudogene on chromosome 10.^[2]

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.

History

Nampt/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.^[3] Rongvaux et al.^[4] demonstrated genetically that the mouse PBEF gene conferred Nampt enzymatic activity and NAD-independent growth to bacteria lacking nadV. Revollo et al.^[5] determined biochemically that the mouse PBEF gene product encodes a Nampt enzyme, capable of modulating intracellular NAD levels. Others have since confirmed these findings.^[6] 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.^[7][8][9]

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.^[10] In particular, Nampt/PBEF was recently re-identified as a “new visceral fat-derived hormone” named visfatin.^[11] 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.^[11] 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.^[11] 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.^[11][12][13] 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,^[11] who first described Visfatin as a visceral-fat derived hormone that acts by binding and activating the insulin receptor, retracted the entire paper^[11] 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.^[14]

References

1. ^ ^{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". Mol. Cell. Biol. 14 (2): 1431–7. PMC 358498. PMID 8289818. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=358498. 
2. ^ "Entrez Gene: PBEF1 pre-B-cell colony enhancing factor 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10135. 
3. ^ Martin PR, Shea RJ, Mulks MH (February 2001). "Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence". J. Bacteriol. 183 (4): 1168–74. doi:10.1128/JB.183.4.1168-1174.2001. PMC 94989. PMID 11157928. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=94989. 
4. ^ Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F (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". Eur. J. Immunol. 32 (11): 3225–34. doi:10.1002/1521-4141(200211)32:11<3225::AID-IMMU3225>3.0.CO;2-L. PMID 12555668. 
5. ^ Revollo JR, Grimm AA, Imai S (December 2004). "The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells". J. Biol. Chem. 279 (49): 50754–63. doi:10.1074/jbc.M408388200. PMID 15381699. 
6. ^ 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". Circ. Res. 97 (1): 25–34. doi:10.1161/01.RES.0000173298.38808.27. PMID 15947248. 
7. ^ Wang T, Zhang X, Bheda P, Revollo JR, Imai S, Wolberger C (July 2006). "Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme". Nat. Struct. Mol. Biol. 13 (7): 661–2. doi:10.1038/nsmb1114. PMID 16783373. 
8. ^ 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". J. Mol. Biol. 362 (1): 66–77. doi:10.1016/j.jmb.2006.06.082. PMID 16901503. 
9. ^ Khan JA, Tao X, Tong L (July 2006). "Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents". Nat. Struct. Mol. Biol. 13 (7): 582–8. doi:10.1038/nsmb1105. PMID 16783377. 
10. ^ 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". J. Clin. Invest. 113 (9): 1318–27. doi:10.1172/JCI19930. PMC 398427. PMID 15124023. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=398427. 
11. ^ ^{a b c d e f} 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 (January 2005). "Visfatin: a protein secreted by visceral fat that mimics the effects of insulin". Science 307 (5708): 426–30. doi:10.1126/science.1097243. PMID 15604363. 
12. ^ 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". Curr. Opin. Lipidol. 17 (2): 128–31. doi:10.1097/01.mol.0000217893.77746.4b. PMID 16531748. 
13. ^ Arner P (January 2006). "Visfatin--a true or false trail to type 2 diabetes mellitus". J. Clin. Endocrinol. Metab. 91 (1): 28–30. doi:10.1210/jc.2005-2391. PMID 16401830. 
14. ^ 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. doi:10.1126/science.318.5850.565b. PMID 17962537. 

Further reading

• Preiss J and Handler P (1957). "Enzymatic synthesis of nicotinamide mononucleotide". J. Biol. Chem. 225: 759–770. 
• Stephens JM, Vidal-Puig AJ (2007). "An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity.". Curr. Opin. Lipidol. 17 (2): 128–31. doi:10.1097/01.mol.0000217893.77746.4b. PMID 16531748. 
• Bełtowski J (2006). "Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity?". Med. Sci. Monit. 12 (6): RA112–9. PMID 16733497. 
• Pilz S, Mangge H, Obermayer-Pietsch B, März W (2007). "Visfatin/pre-B-cell colony-enhancing factor: a protein with various suggested functions.". J. Endocrinol. Invest. 30 (2): 138–44. PMID 17392604. 
• Siderovski DP, Blum S, Forsdyke RE, Forsdyke DR (1991). "A set of human putative lymphocyte G0/G1 switch genes includes genes homologous to rodent cytokine and zinc finger protein-encoding genes.". DNA Cell Biol. 9 (8): 579–87. doi:10.1089/dna.1990.9.579. PMID 1702972. 
• "Toward a complete human genome sequence.". Genome Res. 8 (11): 1097–108. 1999. doi:10.1101/gr.8.11.1097. PMID 9847074. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• Rongvaux A, Shea RJ, Mulks MH, et al. (2003). "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.". Eur. J. Immunol. 32 (11): 3225–34. doi:10.1002/1521-4141(200211)32:11<3225::AID-IMMU3225>3.0.CO;2-L. PMID 12555668. 
• Scherer SW, Cheung J, MacDonald JR, et al. (2003). "Human chromosome 7: DNA sequence and biology.". Science 300 (5620): 767–72. doi:10.1126/science.1083423. PMC 2882961. PMID 12690205. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2882961. 
• Kitani T, Okuno S, Fujisawa H (2003). "Growth phase-dependent changes in the subcellular localization of pre-B-cell colony-enhancing factor.". FEBS Lett. 544 (1–3): 74–8. doi:10.1016/S0014-5793(03)00476-9. PMID 12782293. 
• Hillier LW, Fulton RS, Fulton LA, et al. (2003). "The DNA sequence of human chromosome 7". Nature 424 (6945): 157–64. doi:10.1038/nature01782. PMID 12853948. 
• Reuter TY, Medhurst AL, Waisfisz Q, et al. (2003). "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Exp. Cell Res. 289 (2): 211–21. doi:10.1016/S0014-4827(03)00261-1. PMID 14499622. 
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039. 
• Jia SH, Li Y, Parodo J, et al. (2004). "Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis". J. Clin. Invest. 113 (9): 1318–27. doi:10.1172/JCI19930. PMC 398427. PMID 15124023. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=398427. 
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928. 
• Rush J, Moritz A, Lee KA, et al. (2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nat. Biotechnol. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455. 
• Fukuhara A, Matsuda M, Nishizawa M, et al. (2005). "Visfatin: a protein secreted by visceral fat that mimics the effects of insulin". Science 307 (5708): 426–30. doi:10.1126/science.1097243. PMID 15604363. 
• Janssen JJ, Klaver SM, Waisfisz Q, et al. (2005). "Identification of genes potentially involved in disease transformation of CML". Leukemia 19 (6): 998–1004. doi:10.1038/sj.leu.2403735. PMID 15815727. 
• van der Veer E, Nong Z, O'Neil C, et al. (2005). "Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation". Circ. Res. 97 (1): 25–34. doi:10.1161/01.RES.0000173298.38808.27. PMID 15947248. 
• Ognjanovic S, Ku TL, Bryant-Greenwood GD (2005). "Pre-B-cell colony-enhancing factor is a secreted cytokine-like protein from the human amniotic epithelium". Am. J. Obstet. Gynecol. 193 (1): 273–82. doi:10.1016/j.ajog.2004.11.003. PMC 1382169. PMID 16021090. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1382169. 

External links

• MeSH visfatin,+human