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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.

Expression & Regulation

NAMPT is downregulated by an increase of miR-34a in obesity via a 3'UTR functional binding site of NAMPT mRNA resulting in a reduction of NAD(+) and decreased SIRT1 activity.^[2]

Reaction

NAmPRTase catalyzes the following chemical reaction:

nicotinamide D-ribonucleotide + diphosphate 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.^[3]

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.^[4] Rongvaux et al.^[5] demonstrated genetically that the mouse PBEF gene conferred Nampt enzymatic activity and NAD-independent growth to bacteria lacking nadV. Revollo et al.^[6] determined biochemically that the mouse PBEF gene product encodes a Nampt enzyme, capable of modulating intracellular NAD levels. Others have since confirmed these findings.^[7] 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.^[8]^[9]^[10]

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.^[11] In particular, Nampt/PBEF was recently re-identified as a “new visceral fat-derived hormone” named visfatin.^[12] 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.^[12] 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.^[12] 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.^[12]^[13]^[14] 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,^[12] who first described Visfatin as a visceral-fat derived hormone that acts by binding and activating the insulin receptor, retracted the entire paper^[12] 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.^[15]

References

^ ^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.
^ Choi SE, Fu T, Seok S, Kim DH, Yu E, Lee KW, Kang Y, Li X, Kemper B, Kemper JK (December 2013). "Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT". Aging Cell. 12 (6): 1062–72. doi:10.1111/acel.12135. PMID 23834033.
^ "Entrez Gene: PBEF1 pre-B-cell colony enhancing factor 1".
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ ^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. (Retracted, see PMID 17962537)
^ 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.
^ 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.
^ 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.

External links

visfatin, human at the US National Library of Medicine Medical Subject Headings (MeSH)
NAMPT human gene location in the UCSC Genome Browser.
NAMPT human gene details in the UCSC Genome Browser.

UpToDate Contents

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English Journal

Increased Nicotinamide Phosphoribosyltransferase in Rhabdomyosarcomas and Leiomyosarcomas Compared to Skeletal and Smooth Muscle Tissue.

Vora M1, Ansari J2, Shanti RM3, Veillon D1, Cotelingam J1, Coppola D4, Shackelford RE1.
Anticancer research.Anticancer Res.2016 Feb;36(2):503-7.
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in NAD synthesis and is up-regulated in several human malignancies, including breast, colon, prostate, thyroid, gastric, and several hematopoietic malignancies. In some malignancies, such as gastric, thyroid, and prostat
PMID 26851003

Identification of benzothiophene amides as potent inhibitors of human nicotinamide phosphoribosyltransferase.

Chen W1, Dong G1, He S1, Xu T1, Wang X1, Liu N1, Zhang W1, Miao C2, Sheng C3.
Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2016 Feb 1;26(3):765-8. doi: 10.1016/j.bmcl.2015.12.101. Epub 2015 Dec 29.
Nicotinamide phosphoribosyltransferase (Nampt) is an attractive therapeutic target for cancer. A Nampt inhibitor with novel benzothiophene scaffold was discovered by high throughput screening. Herein the structure-activity relationship of the benzothiophene Nampt inhibitor was investigated. Several
PMID 26755394

Structural Insights into the Quaternary Catalytic Mechanism of Hexameric Human Quinolinate Phosphoribosyltransferase, a Key Enzyme in de novo NAD Biosynthesis.

Youn HS1,2, Gyun Kim T1,2, Kim MK1, Bu Kang G1, Youn Kang J1,2, Lee JG1,2, Yop An J1,2, Ryoung Park K1,2, Lee Y1,2, Jun Im Y3, Hyuck Lee J4,5, Hyun Eom S1,2,6.
Scientific reports.Sci Rep.2016 Jan 25;6:19681. doi: 10.1038/srep19681.
Quinolinate phosphoribosyltransferase (QPRT) catalyses the production of nicotinic acid mononucleotide, a precursor of de novo biosynthesis of the ubiquitous coenzyme nicotinamide adenine dinucleotide. QPRT is also essential for maintaining the homeostasis of quinolinic acid in the brain, a possible
PMID 26805589

Japanese Journal

11.細胞外Nicotinamide phosphoribosyltransferaseの生理的意義について(第423回研究協議会研究発表要旨,ビタミンB研究委員会)

土屋美加子
ビタミン 85(3), 156-157, 2011-03-25
NAID 110008607872

Structure and reaction mechanism of human nicotinamide phosphoribosyltransferase

TAKAHASHI Ryo,NAKAMURA Shota,NAKAZAWA Takashi,MINOURA Katsuhiko,YOSHIDA Takuya,NISHI Yoshinori,KOBAYASHI Yuji,OHKUBO Tadayasu
The journal of biochemistry 147(1), 95-107, 2010-01-01
NAID 10027873352

魚類における3-ヒドロキシアンスラニル酸オキシゲナーゼ/アミノカルボキシムコン酸セミアルデヒド脱炭酸酵素活性比からのトリプトファン-ニコチンアミド変換率の推定

福渡努,真藤こず恵,太田万理,佐々木隆造,柴田克己
ビタミン 78(8), 409-411, 2004-08-25
… In order to estimate the conversion efficiency of tryptophan-nicotinamide in freshwater fishes, carp and crucian, the liver 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO) and aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) activities were measured. … These values were extremely low compared with that of rat (650), which can synsthesize a significant amount of nicotinamide from tryptophan. …
NAID 110002843398

「ニコチンアミドホスホリボシルトランスフェラーゼ」

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PMC	articles
PubMed	articles
NCBI	proteins

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
NCBI	proteins

Nicotinamide phosphoribosyltransferase
	; PDB rendering based on 2g95.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2E5B, 2E5C, 2E5D, 2GVG, 2GVJ, 3DGR, 3DHD, 3DHF, 3DKJ, 3DKL, 4JNM, 4JR5, 4KFN, 4KFO, 4KFP, 4LV9, 4LVA, 4LVB, 4LVD, 4LVF, 4LVG, 4M6P, 4M6Q
Identifiers
Symbols	NAMPT ; 1110035O14Rik; PBEF; PBEF1; VF; VISFATIN
External IDs	OMIM: 608764 MGI: 1929865 HomoloGene: 4201 ChEMBL: 1744525 GeneCards: NAMPT Gene
EC number	2.4.2.12
Gene ontology
Molecular function	• nicotinate-nucleotide diphosphorylase (carboxylating) activity; • nicotinate phosphoribosyltransferase activity; • cytokine activity; • nicotinamide phosphoribosyltransferase activity;
Cellular component	• 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; • NAD metabolic process; • small molecule metabolic process; • positive regulation of transcription from RNA polymerase II promoter; • positive regulation of nitric-oxide synthase biosynthetic process; • adipose tissue development;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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　　[★]

英: nicotinamide phosphoribosyltransferase

「phosphoribosyltransferase」

　　[★] ホスホリボシルトランスフェラーゼ、ホスホリボシル基転移酵素

「nicotinamide」

　　[★] ニコチンアミド、ニコチン酸アミド

[Samal_1994-1] 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.

[pmid23834033-2] Choi SE, Fu T, Seok S, Kim DH, Yu E, Lee KW, Kang Y, Li X, Kemper B, Kemper JK (December 2013). "Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT". Aging Cell. 12 (6): 1062–72. doi:10.1111/acel.12135. PMID 23834033.

[entrez-3] "Entrez Gene: PBEF1 pre-B-cell colony enhancing factor 1".

[pmid11157928-4] 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.

[pmid12555668-5] 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.

[pmid15381699-6] 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.

[pmid15947248-7] 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.

[pmid16783373-8] 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.

[pmid16901503-9] 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.

[pmid16783377-10] 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.

[pmid15124023-11] 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.

[pmid15604363-12] ^ ^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. (Retracted, see PMID 17962537)

[pmid16531748-13] 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.

[pmid16401830-14] 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.

[pmid17962537-15] 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.

リンク元	「ニコチンアミドホスホリボシルトランスフェラーゼ」
関連記事	「phosphoribosyltransferase」「nicotinamide」

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nicotinamide phosphoribosyltransferase