Derivatives of Di-O-octanoylglycerol and mono-O-octylglycerol as modulators of protein kinase C and diacylglycerol kinase activities
Derivatives of Di-O-octanoylglycerol and mono-O-octylglycerol as modulators of protein kinase C and diacylglycerol kinase activities
复制标题
作为蛋白激酶 C 和二酰甘油激酶活性调节剂的二-O-辛酰甘油和单-O-辛酰甘油的衍生物
作者：
Jacqueline Goddat;H. Coste;I. Vilgrain;E. Chambaz;H. Driguez
合成了12个C-3修饰的1，2-二-O-辛酰基甘油类似物和3个甘油的N-烷基季铵盐衍生物。这些化合物作为钙激活的、磷脂依赖的蛋白激酶C(PKC)和二酰甘油(DAG)激酶活性的潜在调节剂进行了体外测试，以了解这些酶与它们的天然激活剂、抑制剂或底物的分子相互作用。通过测定组蛋白H1的磷酸化来检测PKC活性，并在有或没有1，2-二-O-辛酰甘油类似物和磷脂酰丝氨酸/钙混合物的情况下对合成的化合物进行测试。在合成的各种类似物存在的情况下，通过将磷酸掺入1，2-二-O-油酰基-sn-甘油中来测定DAG激酶的活性。关于PKC活性，分析表明，当1，2-二-O-辛酰甘油类似物在C-3上被不允许氢键的基团修饰时，其活性是不活跃的。在我们的实验条件下，在磷脂酰丝氨酸存在的情况下，被报道为无效的二-O-辛酰基硫甘油能够激活PKC。它与二酰甘油有协同激活作用，对佛波醇酯受体结合部位没有亲和力，表明三辛酰硫甘油与酶的作用部位不同于佛波醇酯受体结合部位。双烷基铵化合物(IC5024μM)只有在甘油主链的1-和2-位存在两个8-碳烷基或酰基链时才能抑制PKC和DAG的活性。这些化合物对[~3H]佛波醇12，13-二丁酸酯与蛋白激酶C的结合有很强的作用，也抑制了蛋白激酶C的DAG激酶，这一事实可能提示它们与PKC调节域的DAG位点结合。
Twelve analogs of 1,2-di-O-octanoylglycerol modified at C-3 and three quaternaryN-alkyl-ammonium derivatives of glycerol were synthesized. The compounds were testedin 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 H1 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/Ca2+ 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 thatO-octanoylthioglycerol interacts with the enzyme at a different site from the phorbol ester receptor binding site. PKC and DAG kinase activities are inhibited byN-alkyl-ammonium compounds (IC50 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 [3H]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.
登录
查看更多内容
Sangivamycin 是一种核苷类似物，是蛋白激酶 C 的有效抑制剂。
DOI：
--
发表时间：
1988
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Loomis,CR;Bell,RM
通讯作者：
Bell,RM
DOI：
10.1073/pnas.83.2.241
发表时间：
1986-01-01
影响因子：
11.1
作者：
JEFFREY, AM;LISKAMP, RMJ
通讯作者：
LISKAMP, RMJ
DOI：
10.1073/pnas.83.5.1184
发表时间：
1986-03-01
影响因子：
11.1
作者：
GANONG, BR;LOOMIS, CR;BELL, RM
通讯作者：
BELL, RM
作为蛋白激酶 C 有效抑制剂的新型烷基甘油季铵衍生物的合成和生物活性。
影响因子：
7.3
作者：
MarascoJr,CJ;Piantadosi,C;Meyer,KL;Morris-Natschke,S;Ishaq,KS;Small,GW;Daniel,LW
通讯作者：
Daniel,LW
蛋白激酶 C 的三步纯化程序：纯化酶的表征。
影响因子：
2.9
作者：
Walton,GM;Bertics,PJ;Hudson,LG;Vedvick,TS;Gill,GN
通讯作者：
Gill,GN