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Membrane-surface anchoring of charged diacylglycerol-lactones correlates with biological activities.


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 ?-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.

SUBMITTER: Raifman O 

PROVIDER: S-EPMC3729217 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Membrane-surface anchoring of charged diacylglycerol-lactones correlates with biological activities.

Raifman Or O   Kolusheva Sofiya S   El Kazzouli Said S   Sigano Dina M DM   Kedei Noemi N   Lewin Nancy E NE   Lopez-Nicolas Ruben R   Ortiz-Espin Ana A   Gomez-Fernandez Juan C JC   Blumberg Peter M PM   Marquez Victor E VE   Corbalan-Garcia Senena S   Jelinek Raz R  

Chembiochem : a European journal of chemical biology 20100901 14


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  ...[more]

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