Synthetic branched-chain analogs of distearoylphosphatidylcholine: structure-activity relationship in inhibiting and activating protein kinase C

Abstract

A series of distearoylphosphatidylcholine (DSPC) analogues having various branched alkyl chains were synthesized and tested for their abilities to regulate protein kinase C (PKC). The greatest improvement (about 3-fold) in the PKC inhibitory activity over that seen for the parental lipid (i.e., DSPC) was accomplished by substitution of 8-methylstearate at sn-2 and 16-methylstearate at both sn-1 and sn-2 positions of glycerol; substitutions at both sn-1 and sn-2 with 8-methylstearate, on the other hand, caused a decrease (about 4-fold) in its inhibitory activity. Introduction of butyl, phenyl, or keto functions to various positions in the fatty alkyl chain substituted at both sn-1- and sn-2 positions imparted upon the DSPC analogues an ability to potently stimulate PKC to an extent comparable to those attainable by diacylglycerol or phorbol ester; the analogues having substitution only at the sn-2 position, in comparison, had no or reduced stimulatory activity. The butyl, phenyl, and keto analogues of DSPC, as with DSPC itself and its methyl analogues, inhibited PKC at high concentrations. Kinetic analysis indicated that the methyl DSPC analogues inhibited the enzyme competitively with respect to phosphatidylserine (PS; a phospholipid cofactor) and Ca2+. The butyl analogues activated the enzyme without affecting its affinity for PS or Ca2+, indicating a mechanism different from that seen for diacylglycerol or phorbol ester. The inhibitory activity of the methyl DSPC analogues and the stimulatory activity of the butyl DSPC analogues were reduced when PKC was activated by phorbol ester. Both classes of the analogues were unable to compete for the binding of [3H]phorbol dibutyrate to PKC.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of diacylglycerols on conformation of phosphatidylcholine headgroups in phosphatidylcholine/phosphatidylserine bilayers

“…Such bilayer dehydration could, in principle, favorably change the association of PK-C molecules with the lipids, leading to enzyme activation. It has also been previously shown that PK-C activity is increased by synthetic PC analogues with hydrophobic groups near the headgroups (Charp et al, 1988), which may be due to the promotion of nonbilayer lipid phases by such substitutions (Lewis et al, 1994) and/or a decrease in the association with water molecules. Relatively small numbers of water molecules associated with phosphatidylethanolamine headgroups was suggested to be the cause for the tendency of this lipid to form inverted hexagonal phases (Yeagle and Sen, 1986).…”

Aspects of the Cytological Activity of Edelfosine, Miltefosine, and Ilmofosine in Leishmania Donovani

“…Previous studies (Charp, 1988;Munder and Westphal, 1990;Mollinedo et al, 1993;Engelmann et al, 1996) showed the biphasic effect of these compounds. We can conclude that the doses and the times of incubation could be the key of the use of ALPs.…”

Studies of the thermotropic phase behavior of phosphatidylcholines containing 2-alkyl substituted fatty acyl chains: a new class of phosphatidylcholines forming inverted nonlamellar phases

“…These results are very interesting given our demonstration that the substitution of hydrophobic groups near the polar/apolar interfacial region of the lipid bilayer promotes the formation of nonlamellar phases and previous demonstrations that protein kinase C is activated by nonlamella-forming lipids (see ). Because the possibility that the lipids used by Charp et al, (1988) may have an enhanced nonlamella-forming potential was not recognized by the authors, it would be very interesting if their results were reevaluated with due consideration to the findings presented here.…”

“…Finally, the activity of protein kinase C was recently shown to be increased by diacyl PCs with hydrophobic groups near to the bilayer polar/apolar interface (Charp et al, 1988). These results are very interesting given our demonstration that the substitution of hydrophobic groups near the polar/apolar interfacial region of the lipid bilayer promotes the formation of nonlamellar phases and previous demonstrations that protein kinase C is activated by nonlamella-forming lipids (see ).…”