Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Crystal Structure of Rattus norvegicus Visfatin/PBEF/Nampt in Complex with an FK866-Based Inhibitor

  • Kang, Gil Bu (Department of Life Science, Gwangju Institute of Science and Technology) ;
  • Bae, Man-Ho (Department of Life Science, Gwangju Institute of Science and Technology) ;
  • Kim, Mun-Kyoung (Department of Life Science, Gwangju Institute of Science and Technology) ;
  • Im, Isak (Department of Life Science, Gwangju Institute of Science and Technology) ;
  • Kim, Yong-Chul (Department of Life Science, Gwangju Institute of Science and Technology) ;
  • Eom, Soo Hyun (Department of Life Science, Gwangju Institute of Science and Technology)
  • Received : 2009.02.13
  • Accepted : 2009.04.17
  • Published : 2009.06.30
⟨ Previous Next ⟩

Abstract

Visfatin (Nampt/PBEF) plays a pivotal role in the salvage pathway for $NAD^+$ biosynthesis. Its potent inhibitor, FK866, causes cellular $NAD^+$ levels to decline, thereby inducing apoptosis in tumor cells. In an effort to improve the solubility and binding interactions of FK866, we designed and synthesized IS001, in which a ribose group is attached to the FK866 pyridyl ring. Here, we report the crystal structure of rat visfatin in complex with IS001. Like FK866, IS001 is positioned at the dimer interface, and all of the residues that interact with IS001 are involved in hydrophobic or ${\pi}-{\pi}$-stacking interactions. However, we were unable to detect any strong interactions between the added ribose ring of IS001 and visfatin, which implies that a bulkier modifying group is necessary for a tight interaction. This study provides additional structure-based information needed to optimize the design of visfatin inhibitors.

Keywords

Acknowledgement

Supported by : Ministry for Health, Welfare and Family Affairs

References

  1. Brunger, A.T., Adams, P.D., Clore, G.M., and DeLano, W.L. (1998). Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Cryst. D. 54, 905-921 https://doi.org/10.1107/S0108767398011465
  2. B$\ddot{u}$rkle, A. (2005). Poly(ADP-ribose): The most elaborate metabolite of $NAD^+ $. FEBS J. 272, 4576-4589 https://doi.org/10.1111/j.1742-4658.2005.04864.x
  3. Drevs, J., Loser, R., Rattel, B., and Esser, N. (2003). Antiangiogenic potency of FK866IK22.175, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma. Anticancer Res. 23, 4853-4858
  4. Emsley, P., and Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Cryst. D. 60, 2126-2132 https://doi.org/10.1107/S0907444904019158
  5. Hasmann, M., and Shcemainda, I. (2003). FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res. 63, 7436-7442
  6. Holen, K., Saltz, L.B., Hollywood, E., Burk, K., and Hauske, A.R. (2008). The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest. New Drugs 26, 45-51 https://doi.org/10.1007/s10637-007-9083-2
  7. Hufton, S.E., Moerkerk, P.T., Brandwijk, R., de Bru$\ddot{i}$ne, A.P., Arends, J.W., and Hoogenboom, H.R. (1999). A profile of differentially expressed genes in primary colorectal cancer using suppression subtractive hybridization. FEBS Lett. 463, 77-82 https://doi.org/10.1016/S0014-5793(99)01578-1
  8. Khan, J.A., Tao, X., and Tong, L. (2006). Molecular basis for the inhibition of human visfatin, a novel target for anticancer agents. Nat. Struct. Mol. Biol. 13, 582-586 https://doi.org/10.1038/nsmb1105
  9. Kim, M.K., Lee, J.H., Kim, H., Park, S.J., Kim, S.H., Kang, G.B., Lee, Y.S., Kim, J.B., Kim, K.K., Suh, S.W., et al. (2006). Crystal structure of visfatinIpre-B cell colony enhancing factor 1Inicotinamide phosphoribosyltransferase, free and in complex with the anticancer agent FK-866. J. Mol. Biol. 362, 66-77 https://doi.org/10.1016/j.jmb.2006.06.082
  10. Laskowski, R.A., MacArthur, M.W., Moss, D.S., and Thornton, J.M. (1993). PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Cryst. 26, 283-291 https://doi.org/10.1107/S0021889892009944
  11. Otwinowski, Z., and Minor, W. (1997). Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X
  12. Sanner, M.F. (1999). Python: a programming language for software integration and development. J. Mol. Graphics Mod. 17, 57-61
  13. Schreiber, V., Dantzer, F., Ame, J.C., and de Murcia, G. (2006). Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell. Biol. 7, 517-528 https://doi.org/10.1038/nrm1963
  14. Vagin, A., and Teplyakov, A. (2000). An approach to multi-copy search in molecular replacement. Acta Cryst. D. 56, 1622-1624 https://doi.org/10.1107/S0907444900013780
  15. Van Beijnum, J.R., Moerkerk, P.T., Gerbers, A.J., De Bru$\ddot{i}$ne, A.P., Arends, J.W., Hoogenboom, H.R., and Hufton, S.E. (2002). Target validation for genomics using peptide-specific phage antibodies: a study of five gene products overexpressed in colorectal cancer. Int. J. Cancer 101, 118-127 https://doi.org/10.1002/ijc.10584
  16. Wang, T., Zhang, X., Bheda, P., Revollo, J.R., Imai, S., and Wolberger, C. (2006). Structure of NamptIPBEFIvisfatin, a mammalian $NAD^+$ biosynthetic enzyme. Nat. Struct. Mol. Biol. 13, 661-662 https://doi.org/10.1038/nsmb1114
  17. Won, J., Chung, S.Y., Kim, S.B., Byun, B.H., Yoon, Y.S., and Joe, C.O. (2006). Dose-dependent UV stabilization of p53 in cultured human cells undergoing apoptosis is mediated by poly(ADPribosyl) ation. Mol. Cells 21, 218-223
  18. Wosikowski, K., Mattern, K., Schemainda, I., Hasmann, M., Rattel, B., and L$\ddot{o}$ser, R. (2002). WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells. Cancer Res. 62, 1057-1062
  19. Ziegler, M. (2000). New functions of a long-known molecule. Eur. J. Biochem. 267, 1550-1564 https://doi.org/10.1046/j.1432-1327.2000.01187.x

Cited by

  1. Chemical Proteomics Identifies Nampt as the Target of CB30865, An Orphan Cytotoxic Compound vol.17, pp.6, 2009, https://doi.org/10.1016/j.chembiol.2010.05.008
  2. Target enzyme mutations are the molecular basis for resistance towards pharmacological inhibition of nicotinamide phosphoribosyltransferase vol.10, pp.None, 2009, https://doi.org/10.1186/1471-2407-10-677
  3. Inhibition of Nicotinamide Phosphoribosyltransferase vol.285, pp.44, 2009, https://doi.org/10.1074/jbc.m110.136739
  4. Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methylprop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB-30865) as Potent Inhibitors of Nicotinamide Phosphoribosyltransferase (Nampt) vol.53, pp.24, 2010, https://doi.org/10.1021/jm101145b
  5. Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents vol.46, pp.4, 2009, https://doi.org/10.1016/j.ejmech.2011.01.034
  6. Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway vol.1813, pp.5, 2011, https://doi.org/10.1016/j.bbamcr.2011.02.009
  7. A fluorometric assay for high-throughput screening targeting nicotinamide phosphoribosyltransferase vol.412, pp.1, 2011, https://doi.org/10.1016/j.ab.2010.12.035
  8. Inhibition of nicotinamide phosphoribosyltransferase modifies LPS-induced inflammatory responses of human monocytes vol.18, pp.3, 2012, https://doi.org/10.1177/1753425911423853
  9. PBEF/NAMPT/visfatin: a promising drug target for treating rheumatoid arthritis? vol.4, pp.6, 2009, https://doi.org/10.4155/fmc.12.34
  10. Visfatin and Cardio–Cerebro–Vascular Disease vol.59, pp.1, 2009, https://doi.org/10.1097/fjc.0b013e31820eb8f6
  11. Anti-proliferation effect of APO866 on C6 glioblastoma cells by inhibiting nicotinamide phosphoribosyltransferase vol.674, pp.2, 2012, https://doi.org/10.1016/j.ejphar.2011.11.017
  12. Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors vol.56, pp.16, 2009, https://doi.org/10.1021/jm4001049
  13. Structural and Biochemical Analyses of the Catalysis and Potency Impact of Inhibitor Phosphoribosylation by Human Nicotinamide Phosphoribosyltransferase vol.15, pp.8, 2009, https://doi.org/10.1002/cbic.201402023
  14. New function for Escherichia coli xanthosine phophorylase (xapA): genetic and biochemical evidences on its participation in NAD + salvage from nicotinamide vol.14, pp.None, 2014, https://doi.org/10.1186/1471-2180-14-29
  15. On-Target Effect of FK866, a Nicotinamide Phosphoribosyl Transferase Inhibitor, by Apoptosis-Mediated Death in Chronic Lymphocytic Leukemia Cells vol.20, pp.18, 2009, https://doi.org/10.1158/1078-0432.ccr-14-0624
  16. Physiological and pathophysiological roles of NAMPT and NAD metabolism vol.11, pp.9, 2015, https://doi.org/10.1038/nrendo.2015.117
  17. Chicken Is a Useful Model to Investigate the Role of Adipokines in Metabolic and Reproductive Diseases vol.2018, pp.None, 2018, https://doi.org/10.1155/2018/4579734
  18. Advances in NAD-Lowering Agents for Cancer Treatment vol.13, pp.5, 2009, https://doi.org/10.3390/nu13051665
  19. Nicotinamide phosphoribosyltransferase inhibitor ameliorates mouse aging-induced cognitive impairment vol.41, pp.10, 2009, https://doi.org/10.1177/0271678x211006291
  20. PAK4 and NAMPT as Novel Therapeutic Targets in Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma vol.14, pp.1, 2009, https://doi.org/10.3390/cancers14010160