Photochemical Modulation of Ras-Mediated Signal Transduction Using Caged Farnesyltransferase Inhibitors

Activation by One- and Two-Photon Excitation

Daniel Abate-Pella, Nicholette A. Zeliadt, Joshua D. Ochocki, Janel K. Warmka, Timothy Dore, David A. Blank, Elizabeth V. Wattenberg, Mark D. Distefano

    Research output: Contribution to journalArticle

    Abstract

    The creation of caged molecules involves the attachment of protecting groups to biologically active compounds such as ligands, substrates and drugs that can be removed under specific conditions. Photoremovable caging groups are the most common due to their ability to be removed with high spatial and temporal resolution. Here, the synthesis and photochemistry of a caged inhibitor of protein farnesyltransferase is described. The inhibitor, FTI, was caged by alkylation of a critical thiol group with a bromohydroxycoumarin (Bhc) moiety. While Bhc is well established as a protecting group for carboxylates and phosphates, it has not been extensively used to cage sulfhydryl groups. The resulting caged molecule, Bhc-FTI, can be photolyzed with UV light to release the inhibitor that prevents Ras farnesylation, Ras membrane localization and downstream signaling. Finally, it is shown that Bhc-FTI can be uncaged by two-photon excitation to produce FTI at levels sufficient to inhibit Ras localization and alter cell morphology. Given the widespread involvement of Ras proteins in signal transduction pathways, this caged inhibitor should be useful in a plethora of studies.

    Original languageEnglish (US)
    Pages (from-to)1009-1016
    Number of pages8
    JournalChemBioChem
    Volume13
    Issue number7
    DOIs
    StatePublished - May 7 2012

    Fingerprint

    Farnesyltranstransferase
    Prenylation
    Photochemistry
    ras Proteins
    Signal transduction
    Alkylation
    Ultraviolet Rays
    Photons
    Sulfhydryl Compounds
    Signal Transduction
    Chemical activation
    Phosphates
    Modulation
    Ligands
    Molecules
    Membranes
    Photochemical reactions
    Ultraviolet radiation
    Pharmaceutical Preparations
    Substrates

    Keywords

    • Bromohydroxycoumarin
    • Caged thiol
    • Enzyme inhibitor
    • Farnesylation
    • Photochemistry
    • Ras

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Organic Chemistry

    Cite this

    Abate-Pella, D., Zeliadt, N. A., Ochocki, J. D., Warmka, J. K., Dore, T., Blank, D. A., ... Distefano, M. D. (2012). Photochemical Modulation of Ras-Mediated Signal Transduction Using Caged Farnesyltransferase Inhibitors: Activation by One- and Two-Photon Excitation. ChemBioChem, 13(7), 1009-1016. https://doi.org/10.1002/cbic.201200063

    Photochemical Modulation of Ras-Mediated Signal Transduction Using Caged Farnesyltransferase Inhibitors : Activation by One- and Two-Photon Excitation. / Abate-Pella, Daniel; Zeliadt, Nicholette A.; Ochocki, Joshua D.; Warmka, Janel K.; Dore, Timothy; Blank, David A.; Wattenberg, Elizabeth V.; Distefano, Mark D.

    In: ChemBioChem, Vol. 13, No. 7, 07.05.2012, p. 1009-1016.

    Research output: Contribution to journalArticle

    Abate-Pella, D, Zeliadt, NA, Ochocki, JD, Warmka, JK, Dore, T, Blank, DA, Wattenberg, EV & Distefano, MD 2012, 'Photochemical Modulation of Ras-Mediated Signal Transduction Using Caged Farnesyltransferase Inhibitors: Activation by One- and Two-Photon Excitation', ChemBioChem, vol. 13, no. 7, pp. 1009-1016. https://doi.org/10.1002/cbic.201200063
    Abate-Pella, Daniel ; Zeliadt, Nicholette A. ; Ochocki, Joshua D. ; Warmka, Janel K. ; Dore, Timothy ; Blank, David A. ; Wattenberg, Elizabeth V. ; Distefano, Mark D. / Photochemical Modulation of Ras-Mediated Signal Transduction Using Caged Farnesyltransferase Inhibitors : Activation by One- and Two-Photon Excitation. In: ChemBioChem. 2012 ; Vol. 13, No. 7. pp. 1009-1016.
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