Roberts M F, Wu Y, Zhou C, Geng D, Tan C
Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02167, USA.
Adv Enzyme Regul. 1996;36:57-71. doi: 10.1016/0065-2571(95)00017-8.
PI-specific PLC enzymes are a key component of phosphatidylinositol-mediated signaling pathways since the hydrophobic product, diacylglycerol, activates protein kinase C and the water-soluble product, inositol trisphosphate, is involved in Ca2+ mobilization. Nonspecific, or PC-PLC, enzymes can generate diacylglycerol without Ca2+ mobilization. A series of inhibitors, both lipophilic and water-soluble, have been synthesized to target each of these two classes of PLC enzymes. Design of the inhibitors was based on proposed enzyme mechanisms and available crystal structures. The solution conformations of the lipophilic phospholipid analogs, (diheptanoylphosphatidyl(2-O-methyl)inositol for PI-PLC and a dihexanoyl-sn-(3-N-benzylaminoglycero)phosphoramidocholine for PC-PLC, have been determined using NMR methodology and the interaction of these compounds with bacterial enzymes has been examined. Water-soluble inhibitors include strained cyclic phosphonates for PI-PLC and vanadate for PC-PLC. An eventual goal of this work is to generate compounds that specifically target each type of intracellular PLC activity.
磷脂酰肌醇特异性磷脂酶C（PI-specific PLC）是磷脂酰肌醇介导的信号通路的关键组成部分，因为其疏水性产物二酰基甘油可激活蛋白激酶C，而水溶性产物三磷酸肌醇则参与钙离子动员。非特异性的，即磷脂酰胆碱特异性磷脂酶C（PC-PLC），可在不进行钙离子动员的情况下生成二酰基甘油。已经合成了一系列亲脂性和水溶性抑制剂，以针对这两类磷脂酶C。抑制剂的设计基于推测的酶作用机制和可用的晶体结构。利用核磁共振方法确定了亲脂性磷脂类似物的溶液构象（用于PI-PLC的二庚酰磷脂酰（2-O-甲基）肌醇和用于PC-PLC的二己酰-sn-（3-N-苄基氨基甘油）磷酰胺胆碱），并研究了这些化合物与细菌酶的相互作用。水溶性抑制剂包括用于PI-PLC的张力环状膦酸酯和用于PC-PLC的钒酸盐。这项工作的最终目标是生成能够特异性靶向每种细胞内PLC活性类型的化合物。
