title: 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 α-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.
authors: Department of Chemistry, Ben Gurion University, Beer Sheva 84105, Israel.
authors: Or
authors: O
authors: Raifman
authors: Sofiya
authors: S
authors: Kolusheva
authors: Said
authors: S
authors: El Kazzouli
authors: Dina M
authors: DM
authors: Sigano
authors: Noemi
authors: N
authors: Kedei
authors: Nancy E
authors: NE
authors: Lewin
authors: Ruben
authors: R
authors: Lopez-Nicolas
authors: Ana
authors: A
authors: Ortiz-Espin
authors: Juan C
authors: JC
authors: Gomez-Fernandez
authors: Peter M
authors: PM
authors: Blumberg
authors: Victor E
authors: VE
authors: Marquez
authors: Senena
authors: S
authors: Corbalan-Garcia
authors: Raz
authors: R
authors: Jelinek
mesh_terms: D000818:Animals; D002152:Calorimetry, Differential Scanning; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D004075:Diglycerides / Q000737:chemistry / Q000378:metabolism*; D007783:Lactones / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D011493:Protein Kinase C / Q000032:analysis / Q000378:metabolism; D051381:Rats
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D007783:Lactones; D011493:Protein Kinase C