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Derivatives of Di‐ O ‐octanoylglycerol and mono‐ O ‐octylglycerol as modulators of protein kinase C and diacylglycerol kinase activities
Author(s) -
Goddat Jacqueline,
Coste Hervé,
Vilgrain Isabelle,
Chambaz Edmond,
Driguez Hugues
Publication year - 1992
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/bf02536146
Subject(s) - diacylglycerol kinase , protein kinase c , lipidology , kinase , diglyceride , clinical chemistry , chemistry , microbiology and biotechnology , biochemistry , biology , enzyme
Twelve analogs of 1,2‐di‐ O ‐octanoylglycerol modified at C‐3 and three quaternary N ‐alkyl‐ammonium derivatives of glycerol were synthesized. The compounds were tested in vitro as potential modulators of the calcium activated, phospholipid dependent protein kinase C (PKC) and diacylglycerol (DAG) kinase activities in order to understand the molecular interactions of these enzymes with their natural activators, inhibitors, or substrates. PKC activity was assayed by measuring histone H 1 phosphorylation, and the compounds synthesized were tested either in the presence (inhibitors) or in the absence (activators) of 1,2‐di‐ O ‐octanoyglycerol analogs with the phosphatidylserine/Ca 2+ mixture. DAG kinase activity was measured by the incorporation of phosphate into 1,2‐di‐ O ‐oleoyl‐ sn ‐glycerol in the presence of the various analogs synthesized. In regard to PKC activity, the assays revealed that 1,2‐di‐ O ‐octanoylglycerol analogs are inactive when modified at C‐3 with groups which do not permit hydrogen bonding. Under our conditions, di‐ O ‐octanoylthioglycerol, which has been reported as inactive, was able to activate PKC in the presence of phosphatidylserine. It has been shown to give a synergistic activation with diacylglycerol and had no affinity for the phorbol ester receptor binding site, suggesting that O ‐octanoylthioglycerol interacts with the enzyme at a different site from the phorbol ester receptor binding site. PKC and DAG kinase activities are inhibited by N ‐alkyl‐ammonium compounds (IC 50 24 μM) only when either two 8‐carbon alkyl or acyl chains are present at the 1‐ and 2‐positions of the glycerol backbone. The fact that these compounds have a strong effect on the binding of [ 3 H]phorbol 12,13‐dibutyrate to protein kinase C, and also inhibit DAG kinase, may suggest binding to the DAG site of the regulatory domain of PKC.