|pre-B-cell colony enhancing factor 1|
|Locus||Chr. 7 q22.2|
Nampt, PBEF, and visfatin refer to an identical protein, as judged by its amino acid sequence, with multiple biological functions. Nampt/PBEF/visfatin is a nicotinamide phosphoribosyltransferase (Nampt) enzyme that catalyzes first step in the biosynthesis of NAD from nicotinamide. This protein has also been reported to be a cytokine (PBEF) that promotes B cell maturation and inhibits neutrophil apoptosis, or a visceral-fat derived hormone (visfatin) that acts by binding and activating the insulin receptor.
Nampt/PBEF/visfatin was originally cloned as a putative cytokine shown to enhance the maturation of B cell precursors in the presence of Interleukin (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 (2). Rongvaux et al. (3) demonstrated genetically that the mouse PBEF gene conferred Nampt enzymatic activity and NAD-independent growth to bacteria lacking nadV. Revollo et al. (4) determined biochemically that the mouse PBEF gene product encodes a Nampt enzyme, capable of modulating intracellular NAD levels. Others have since confirmed these findings (5). 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 (6, 7, 8).
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 (9). Particularly, Nampt/PBEF was recently re-identified as a “new visceral fat-derived hormone” named visfatin (10). 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 (10). Strikingly, 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 (10). 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 (10, 11, 12). Additionally, the ability of visfatin to bind and activate the insulin-receptor has yet to be confirmed by other groups.
1. Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I. (1994) Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol. 14:1431-7.
2. Martin PR, Shea RJ, Mulks MH. (2001) Identification of a plasmid-encoded gene from Haemophilus ducreyi which confers NAD independence. J Bacteriol. 183:1168-74.
3. Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F. (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. 32:3225-34.
4. Revollo JR, Grimm AA, Imai S. (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem. 279:50754-63.
5. van der Veer E, Nong Z, O'Neil C, Urquhart B, Freeman D, Pickering JG. (2005) Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation. Circ Res. 97:25-34.
6. Wang T, Zhang X, Bheda P, Revollo JR, Imai S, Wolberger C. (2006) Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme. Nat Struct Mol Biol. 13:661-2.
7. Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, Lee YS, Kim JB, Kim KK, Suh SW, Eom SH. (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. 362:66-77.
8. Khan JA, Tao X, Tong L. (2006) Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents. Nat Struct Mol Biol. 13:582-8.
9. Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD, Marshall JC. (2004) Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. J Clin Invest. 113:1318-27.
10. 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. (2005) Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307:426-30.
11. Stephens JM, Vidal-Puig AJ. (2006) An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity. Curr Opin Lipidol. 17:128-31.
12. Arner P. (2006) Visfatin--a true or false trail to type 2 diabetes mellitus. J Clin Endocrinol Metab. 91:28-30.