Nicotinamide phosphoribosyltransferase

Nicotinamide phosphoribosyltransferase

PDB rendering based on 2g95.
Available structures
PDB Ortholog search: PDBe, RCSB
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
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 10135 59027
Ensembl ENSG00000105835 ENSMUSG00000020572
UniProt P43490 Q99KQ4
RefSeq (mRNA) NM_005746 NM_021524
RefSeq (protein) NP_005737 NP_067499
Location (UCSC) Chr 7:
106.25 – 106.29 Mb		 Chr 12:
32.82 – 32.85 Mb
PubMed search
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

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 \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.[3]

Nomenclature

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

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]

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.[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]

As a drug target

APO866 is an experimental drug that inhibits this enzyme.[16] It is being tested for treatment of advanced melanoma, cutaneous T-cell lymphoma (CTL), and refractory or relapsed B-chronic lymphocytic leukemia.

References

  1. 1 2 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.
  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.
  3. ↑ "Entrez Gene: PBEF1 pre-B-cell colony enhancing factor 1".
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  12. 1 2 3 4 5 6 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)
  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.
  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.
  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.
  16. ↑ APO866 Not Effective for Cutaneous T-Cell Lymphoma. March 2016

Further reading

External links

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