Skip to main content
SpringerLink
Log in

Chemistry and biology of ras farnesyltransferase

  • Research Article Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Mutated forms of ras are found in many human tumors and the rate of incidence is significantly higher in colon and pancreatic cancers. The protein product from theras oncogene is a small G-protein, p21ras(Ras) that is known to play a key role in the signal transduction cascade and cell differentiation and proliferation. Mutated Ras is unable to regulate itself and remains constantly activated, leading to uncontrolled cell growth. The function of Ras in signal transduction requires its location near the growth factor receptor at the cell membrane. However, Ras does not have a transmembrane domain. Ras requires farnesylation to increase its hydrophobicity and subsequent plasma membrane association for its transforming activity. This key post-translational modification is catalyzed by the enzyme Ras farnesyltransferase (FTase), which transfers a farnesyl group from famesylpyrophosphate to theC-terminal cysteine of the Ras protein. The requirement has focused attention on FTase as a target for therapeutic intervention. Selective inhibition of FTase will prevent Ras protein from association with the plasma membrane, leading to a disruption of oncogenic Ras function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Barbacid, M., Ras gene.Annu. Rev. Biochem., 56, 779–827 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Barinaga, M., From bench top to bedside.Science, 278, 1036–1039 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Bolton, G. L., Sebolt-Leopold, J. S. and Hodges, J. C., In Bristol, J. A. (Ed.),Annual reports in Medicinal Chemistry, vol. 29, Academic Press, New York, pp165–174, (1994).

    Google Scholar 

  • Bos, J. L., Ras Oncogenes in human cancer.Cancer Res., 49, 4682–4689 (1989).

    PubMed  CAS  Google Scholar 

  • Brown, M. S., Goldstein, J. L., Paris, K. J., Burnier, J. P. and Marsters, J. J., Tetrapeptide inhibitors of protein farnesy-Itransferase: Amino-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation.Proc. Natl. Acad.Sci. USA, 89, 8313–8316 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Burn, C. J., Guitton, J.-D., Baudoin, B., Lelievre, Y., Duchesne, M., Parker, F., Fromage, N. and Commercon, A., Novel conformationally extended naphthalene-based inhibitors of farnesyltransferase.J. Med. Chem., 40, 1763–1767 (1997).

    Article  Google Scholar 

  • Buss, J. E. and Marsters, J. C., Jr., Farnesyl transferase inhibitors: The successes and surprises of new class of potential cancer chemotherapeutics.Chemistry & Biology, 2, 787–791 (1995).

    Article  CAS  Google Scholar 

  • Cadena, D. L. and Gill, G. N., Receptor tyrosine kinases.FASEB J., 6, 2332–2337 (1992).

    PubMed  CAS  Google Scholar 

  • Casey, P. J., Biochemistry of protein prenylation.J. Lipid Res., 33, 1731–1740 (1992).

    PubMed  CAS  Google Scholar 

  • Casey, P. J. and Seabra, M. C., Protein prenyltransferases.J. Biol. Chem., 271, 5289–5292 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Casey, P. J., Solski, P. A., Der, C. J. and Buss, J. E., p21 Ras is modified by a farnesyl isoprenoid.Proc. Natl. Acad. Sci. USA, 86, 8323–8327 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Clerc, F.-F., Guitton, J.-D., Fromage, N., Lelievre, Y., Duchesne, M., Tocque, B., James-Surcouf, E., Commercon, A. and Becquart, J., Constrained analogues of kcvfmwith improved inhibitory properties against farnesyltransferase.Bioorg. Med.Chem., 5, 1779–1784 (1995).

    Article  CAS  Google Scholar 

  • Cox, A. D. and Der, C. J., Farnesyltransferase inhibitors and cancer treatment: Targeting simply Ras?.Biochim. Biophy. Acta., 1333, F51-F71 (1997).

    CAS  Google Scholar 

  • Der, C. J. and Cox, A. D., Isoprenoid modification and plasma membrane association: critical factors for ras oncogenicity.Cancer Cells, 3, 331–340 (1991).

    PubMed  CAS  Google Scholar 

  • Dolence, J. M. and Poulter, C. D., A mechanism for posttranslational modifications of proteins by yeast protein farnesyltransferase.Proc. Natl. Acad. Sci. USA, 92, 5008–5011 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Dunten, P., Kammlott, U., Crowther, R., Weber, D., Palermo, R. and Birktoft, J., Protein farnesyltransferase: Structure and implications for substrate binding.Biochemistry, 37, 7907–7912 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Edelstein, R. L., Weller, V. A. and Distefano, M. D., Stereo-chemical analysis of the reaction catalyzed by yeast protein farnesyltransferase.J. Org. Chem., 63, 5298–5299 (1998).

    Article  CAS  Google Scholar 

  • Fearon, E. R., Human cancer syndromes.Science, 278, 1043–1050 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Fu, H.-W., Beese, L. S. and Casey, P. J., Kinetic analysis of zinc ligand mutants of mammalian protein farnesyltransferase.Biochemistry, 37, 4465–4472 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Gibbs, J. B., Graham, S. L., Hartman, G. D., Koblan, K. S., Kohl, N. E., Omer, C. A. and Oliff, A., Farnesyltransferase inhibitors versus Ras inhibitors.Curr. Opin. Chem. Biol., 1, 197–203 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Grand, R. J. A. and Owen D., The biochemistry of ras p21.Biochem. J., 279, 609–631 (1991).

    PubMed  CAS  Google Scholar 

  • Gutierrez, L., Magee, A. I., Marshall, C. J. and Hancock, J. F., Post-translational processing of p21 ras is two-step and involves carboxyl-methylation and carboxyterminal proteolysis.EMBO J., 8, 1093–1098 (1989).

    PubMed  CAS  Google Scholar 

  • Hamilton, A. D. and Sebti, S. M., Inhibitors of Ras farnesyltransferase as novel antitumor agents.Drug News Perspect., 8, 138–145 (1995).

    Google Scholar 

  • Hancock, J. F., Magee, A. I., Childs, J. E. and Marshall, C. J., All ras proteins are polyisoprenylated but only some are palmitoylated.Cell, 57, 1167–1177 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Heldin, C.-H. and Westermark B., Signal transduction by the receptors for plateleWerived growth factor.J. Cell Sci., 96, 193–196 (1990).

    PubMed  CAS  Google Scholar 

  • Hightower, K. E. and Fierke, C. A., Zinc-catalyzed sulfur alkylation: Insights from protein farnesyltransferase..Curr. Opin. Chem. Biol., 3, 176–181 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Hightower, K. E., Huang, C.-C., Casey, R J. and Fierke, C. A., H-Ras peptide and protein substrates bind protein farnesyltransferase as an ionized thiolate.Biochemistry, 37, 15555–15562 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Hinterding, K., Alonso-Diaz, D. and Waldmann, H., Organic synthesis and biological signal transduction.Angew. Chem. Int. Ed. Engl., 37, 688–749 (1998).

    Article  CAS  Google Scholar 

  • Hunt, J. T., Lee, Y. G., Leftheris, K., Seizinger, B., Carboni, J., Mabus, J., Ricca, C., Yan, N. and Manne, V., Potent, cell active, non-thiol tetrapeptide inhibitors offarnesyltransferase.J. Med. Chem., 39, 353–358 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Kobran, K. S., Culberson, J. C., Desolms, S. J., Giuliani, E. A., Mosser, S. D., Omer, CA., Pitzenberger, S. M. and Bogusky, M. J., NMR studies of novel inhibitors bound to farnesyl protein transferase.Protein Sci., 4, 681–688 (1995).

    Google Scholar 

  • Krengel, U., Schlichting, I., Scherer, A., Schumann, R., French, M., John, J., Kabsch, W., Pai, E. F. and Wittinghofer, A., Three-dimensional structures of H-ras p21 mutants: Molecular basis for their inability to function as signal switch molecules.Cell, 62, 539–548 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Leonard, D. M., Ras farnesyltransferase: A new therapeutic target.J. Med. Chem., 40, 2971–2990 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Leonard, D. M., Shuler, K. R., Poulter, C. J., Eaton, S. R., Sawyer, T. K., Hodges, J. C., Su, T.-Z., Scholten, J. D., Gowan, R. C., Sebolt-Leopold, J. S. and Doherty, A. M., Structure-activity relationships of cysteine-locking pentapeptide derivatives that inhibit ras farnesyltransferase.J. Med. Chem., 40, 192–200 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Long, S. B. and Casey, P. J., Cocrystal structure of protein farnesyltransferase complexed with a farnesyl diphosphate substrate.Biochemistry, 37, 9612–9618 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Lowy, D. R. and Willumsen, B. M., Function and regulation of Ras.Annu. Rev. Biochem., 62, 851–891 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Maignan, S., Guilloteau, J.-P., Fromage, N., Arnoux, B., Becquart, J. and Ducruix, A., Crystal structure of the mammalian Grb2 adaptor.Science, 268, 291–293 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Masrers, J. C., Jr., McDowell, R. S., Reynilds, M. E., Oare, D. A., Somers, T. C., Stanley, M. S., Rawson, T. E., Struble, M. E., Burdick, D. J., Chan, K. S., Duarte, C. M., Paris, K. J., Tom, J. Y., Wan, D. T., Xue, Y. and Burnier, J. P., Benzodiazepine peptidomimetic inhibitors of farnesylferase.Bioorg. Med. Chem., 2, 949–957 (1994).

    Article  Google Scholar 

  • Matthews, R. G. and Goulding, C. W., Enzyme-catalyzed methyl transfers to thiols: Therole of zinc.Curr. Opin. Chem. Biol., 1, 332–339 (1997).

    Article  PubMed  CAS  Google Scholar 

  • McCormick, F., Ras GTPase activating protein: Signal transmitter and signalterminator.Cell, 56, 5–8 (1989).

    Article  PubMed  CAS  Google Scholar 

  • McCormick, F., How receptors turn Ras on.Nature, 363, 15–16 (1993).

    Article  PubMed  CAS  Google Scholar 

  • McCormick, F., Raf: The holy grail of Ras biology?.Trends Cell Biol., 1994, 4, 347–350 (1994).

    Article  CAS  Google Scholar 

  • Moodie, S. A. and Wolfman, A., The 3Rs of life: Ras, Raf and Growth regulation.TIG, 10, 44–48 (1994).

    PubMed  CAS  Google Scholar 

  • Mu, Y., Omer, C. A. and Gibbs, R. A., On the stereochemical course of human protein farnesyltransferaes.J. Am. Chem. Soc., 118, 1817–1823 (1996).

    Article  CAS  Google Scholar 

  • Pai, E. F., Krengel, U., Gregoty, A. P., Goody, R. S., Kabsch, W. and Wittinghofer, A., Refiend crystal Structure of the triphosphate conformation of H-ras p21 at 1.35 Aresolution: Implications for the mechanism of GTP hydrolysis.EMBO J., 9, 2351–2359 (1990).

    PubMed  CAS  Google Scholar 

  • Park, H.-W. and Beese, L. S., Protein farnesyltransferase.Curr. Opin. Struct. Biol., 7, 873–880 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Park, H.-W., Boduluri, S. R., Moornaw, J. P., Casey, P. J. and Beese, L. S., Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution.Science, 275, 1800–1805 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Patel, D. V., Gordon, E. M., Schmidt, R. J., Weller, H. N., Young, M. G., Zahler, R., Barbacid, M., Carboni, J. M., Gullo-Brown, J. L., Huniham, L., Ricca, C., Robinson, S., Seizinger, B. R., Tuomari, A. V. and Mann, V., Phosphinyl acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase.J. Med. Chem., 38, 435–42 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Pawson, T. and Schlessinger, J., SH2 and SH3 domains.J. Curr. Biol. 3, 434–442 (1993).

    Article  CAS  Google Scholar 

  • Reiss, Y., Brown, M. S. and Goldstein, J. L., Divalent cation and prenyl pyrophosphate specificities of the protein farnesyl-transferase from rat brain, a zinc metalloenzyme.J. Biol. Chem., 267, 6403–6408 (1992).

    PubMed  CAS  Google Scholar 

  • Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J. and Brown, M. S., Inhibition of purified p21 ras farnesyl protein transferase by Cys-AAX tetrapeptide.Cell, 62, 81–88 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Strickland, C. L., Windsor, W. T., Syto, R., Wang, L., Bond, R., Wu, Z., Schwartz, J., Le, H. V., Beese, L. S. and Weber, P. C., Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue.Biochemistry, 37, 16601–16611 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Weller, V. A. and Distefano, M. D., Measurement of the α-Secondary kinetic isotope effect for a prenyltransferase by MALDI mass spectrometry.J. Am. Chem. Soc., 120, 7975–7976 (1998).

    Article  CAS  Google Scholar 

  • Willumsen, B. M., Christensen, A., Hubert, N. L., Papageorge, A. G. and Lowy, D. R., The p2.ras C-terminus is required for transformation and membrane association.Nature, 310, 583–586 (1984).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Bio-Organic Science Division, Korea Research Institute of Chemical Technology, P.O.Box 107, 305-600, Yusong, Taejon, Korea

    Kwang -Nym Cho & Kee -In Lee

Authors
  1. Kwang -Nym Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kee -In Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kee -In Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, K.N., Lee, K.I. Chemistry and biology of ras farnesyltransferase. Arch Pharm Res 25, 759–769 (2002). https://doi.org/10.1007/BF02976989

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02976989

Key words

Search

Navigation