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Synthesis and biological activity of phospholipase C-resistant analogues of phosphatidylinositol 4,5-bisphosphate. 2006

Honglu Zhang, and Yong Xu, and Zheng Zhang, and Emily R Liman, and Glenn D Prestwich
Department of Medicinal Chemistry, University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.

The membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) is an important regulator in cell physiology. Hydrolysis of PtdIns(4,5)P2 by phospholipase C (PLC) releases two second messengers, Ins(1,4,5)P3 and diacylglycerol. To dissect the effects of PtdIns(4,5)P2 from those resulting from PLC-generated signals, a metabolically stabilized analogue of PtdIns(4,5)P2 was required. Two analogues were designed in which the scissile O-P bond was replaced with a C-P bond that could not be hydrolyzed by PLC activity. Herein we describe the asymmetric total synthesis of the first metabolically stabilized phospholipase C-resistant analogues of PtdIns(4,5)P2. The key transformation was a Pd(0)-catalyzed coupling of a H-phosphite with a vinyl bromide to form the desired C-P linkage. The phosphonate analogues of PtdIns(4,5)P2 were found to be effective in restoring the sensitivity of the TRPM4 channel to Ca2+ activation.

UI MeSH Term Description Entries
D010738 Type C Phospholipases A subclass of phospholipases that hydrolyze the phosphoester bond found in the third position of GLYCEROPHOSPHOLIPIDS. Although the singular term phospholipase C specifically refers to an enzyme that catalyzes the hydrolysis of PHOSPHATIDYLCHOLINE (EC 3.1.4.3), it is commonly used in the literature to refer to broad variety of enzymes that specifically catalyze the hydrolysis of PHOSPHATIDYLINOSITOLS. Lecithinase C,Phospholipase C,Phospholipases, Type C,Phospholipases C
D050053 TRPM Cation Channels A subgroup of TRP cation channels named after melastatin protein. They have the TRP domain but lack ANKYRIN repeats. Enzyme domains in the C-terminus leads to them being called chanzymes. TRPM Cation Channel,Transient Receptor Potential Channels, Type M,Cation Channel, TRPM,Cation Channels, TRPM,Channel, TRPM Cation,Channels, TRPM Cation
D019269 Phosphatidylinositol 4,5-Diphosphate A phosphoinositide present in all eukaryotic cells, particularly in the plasma membrane. It is the major substrate for receptor-stimulated phosphoinositidase C, with the consequent formation of inositol 1,4,5-triphosphate and diacylglycerol, and probably also for receptor-stimulated inositol phospholipid 3-kinase. (Kendrew, The Encyclopedia of Molecular Biology, 1994) PtdInsP2,Phosphatidylinositol 4,5-Biphosphate,Phosphatidylinositol Phosphate, PtdIns(4,5)P2,Phosphatidylinositol-4,5-Biphosphate,PtIns 4,5-P2,PtdIns(4,5)P2,PtdInsP,4,5-Biphosphate, Phosphatidylinositol,4,5-Diphosphate, Phosphatidylinositol,Phosphatidylinositol 4,5 Biphosphate,Phosphatidylinositol 4,5 Diphosphate

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