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Therapeutic intervention based on protein prenylation and associated modifications

Nature Chemical Biology volume 2, pages 518–528 (2006)Cite this article

Abstract

In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.

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Figure 1: Structures of the C termini of prenylated proteins.
Figure 2: Enzymatic pathway for the modification of prenylated proteins.
Figure 3: Model for the trafficking of H-Ras and N-Ras from the Golgi complex to the plasma membrane and back67,68.
Figure 4: Model for extraction of prenylated Rab proteins from membranes via GDI, as previously formulated87.
Figure 5: Schematic representation of methods used to introduce natural and modified lipidated C termini on Ras GTPases, and a collection of semisynthetic neo-Ras proteins synthesized via these methods58,62,64,67,76.
Figure 6: FTI and GGTI compounds.

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Acknowledgements

This work was supported by US National Institutes of Health grants AI054384 to M.H.G., GM41223 to S.M. and CA32737 and CA41996 to F.T.

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Authors and Affiliations

  1. Departments of Chemistry and Biochemistry, University of Washington, Seattle, 98195, Washington, USA

    Michael H Gelb

  2. Max-Planck Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund and Universität Dortmund, Fachbereich Chemie, Dortmund, Germany

    Lucas Brunsveld & Herbert Waldmann

  3. Department of Chemistry and the Purdue Cancer Center, Purdue University, West Lafayette, 47907, Indiana, USA

    Christine A Hrycyna

  4. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Susan Michaelis

  5. Department of Microbiology, Immunology and Molecular Genetics and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, 90095-1489, California, USA

    Fuyuhiko Tamanoi

  6. Department of Medicine, University of Washington, Seattle, 98195, Washington, USA

    Wesley C Van Voorhis

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Correspondence to Michael H Gelb.

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Gelb, M., Brunsveld, L., Hrycyna, C. et al. Therapeutic intervention based on protein prenylation and associated modifications. Nat Chem Biol 2, 518–528 (2006). https://doi.org/10.1038/nchembio818

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