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Membrane-Surface Anchoring of Charged Diacylglycerol-Lactones Correlates with Biological Activities

  1. Author:
    Raifman, O.
    Kolusheva, S.
    El Kazzouli, S.
    Sigano, D. M.
    Kedei, N.
    Lewin, N. E.
    Lopez-Nicolas, R.
    Ortiz-Espin, A.
    Gomez-Fernandez, J. C.
    Blumberg, P. M.
    Marquez, V. E.
    Corbalan-Garcia, S.
    Jelinek, R.

  2. Author Address

    [El Kazzouli, Said; Sigano, Dina M.; Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Raifman, Or; Kolusheva, Sofiya; Jelinek, Raz] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Kedei, Noemi; Lewin, Nancy E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Lopez-Nicolas, Ruben; Ortiz-Espin, Ana; Gomez-Fernandez, Juan C.; Corbalan-Garcia, Senena] Univ Murcia, Dept Biochem & Mol Biol A, Sch Vet, E-30100 Murcia, Spain.;Marquez, VE, NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA.;marquezv@dc37a.nci.nih.gov senena@um.es razj@bgu.ac.il
    1. Year: 2010
    2. Date: Sep
  2. Journal: Chembiochem
    1. 11
    2. 14
    3. Pages: 2003-2009
  4. Type of Article: Article
  5. ISSN: 1439-4227
  1. Abstract:

    Synthetic diacylglycerol-lactones (DAG-lactones) are effective modulators of critical cellular signaling pathways, downstream of the lipophilic second messenger diacylglycerol, that activate a host of protein kinase C (PKC) isozymes and other nonkinase proteins that share similar C1 membrane-targeting domains with PKC. A fundamental determinant of the biological activity of these amphiphilic molecules is the nature of their interactions with cellular membranes. This study examines the biological properties of charged DAG-lactones exhibiting different alkyl groups attached to the heterocyclic nitrogen of an alpha-pyridylalkylidene chain, and particularly the relationship between membrane interactions of the substituted DAG-lactones and their respective biological activities. Our results suggest that bilayer interface localization of the N-alkyl chain in the R-2 position of the DAG-lactones inhibits translocation of PKC isoenzymes onto the cellular membrane. However, the orientation of a branched alkyl chain at the bilayer surface facilitates PKC binding and translocation. This investigation emphasizes that bilayer localization of the aromatic side residues of positively charged DAG-lactone derivatives play a central role in determining biological activity, and that this factor contributes to the diversity of biological actions of these synthetic biomimetic ligands.

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External Sources

  1. View Full Text
  2. DOI: 10.1002/cbic.201000343
  3. View record in Web of Science®
  4. WOS: 000282596900013

Library Notes

  1. Fiscal Year: FY2009-2010
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