5‐Stabilized Phosphatidylinositol 3,4,5‐Trisphosphate Analogues Bind Grp1 PH,Inhibit Phosphoinositide Phosphatases,and Block Neutrophil Migration |
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Authors: | Honglu Zhang Dr Ju He Dr Tatiana G Kutateladze Prof Dr Takahiro Sakai Dr Takehiko Sasaki Prof Dr Nicolas Markadieu Dr Christophe Erneux Prof Dr Glenn D Prestwich Prof Dr |
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Affiliation: | 1. Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108‐1257 (USA), Fax: (+1)?801‐585‐9053;2. Department of Pharmacology, University of Colorado Denver, School of Medicine, 12801 East 17th Ave, Aurora, CO 80045‐0511 (USA);3. Division of Microbiology, Department of Pathology and Immunology, Akita University School of Medicine, 1‐1‐1 Hondo, 010‐8543, Akita (Japan);4. Department of Cell Physiology and Institut de Recherche Interdisciplinaire (IRIBHM), Université Libre de Bruxelles, Campus Erasme, Route de Lennik 808, 1070 Bruxelles, (Belgium) |
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Abstract: | Metabolically stabilized analogues of PtdIns(3,4,5)P3 have shown long‐lived agonist activity for cellular events and selective inhibition of lipid phosphatase activity. We describe an efficient asymmetric synthesis of two 5‐phosphatase‐resistant analogues of PtdIns(3,4,5)P3, the 5‐methylene phosphonate (MP) and 5‐phosphorothioate (PT). Furthermore, we illustrate the biochemical and biological activities of five stabilized PtdIns(3,4,5)P3 analogues in four contexts. First, the relative binding affinities of the 3‐MP, 3‐PT, 5‐MP, 5‐PT, and 3,4,5‐PT3 analogues to the Grp1 PH domain are shown, as determined by NMR spectroscopy. Second, the enzymology of the five analogues is explored, showing the relative efficiency of inhibition of SHIP1, SHIP2, and phosphatase and tensin homologue deleted on chromosome 10 (PTEN), as well as the greatly reduced ability of these phosphatases to process these analogues as substrates as compared to PtdIns(3,4,5)P3. Third, exogenously delivered analogues severely impair complement factor C5a‐mediated polarization and migration of murine neutrophils. Finally, the new analogues show long‐lived agonist activity in mimicking insulin action in sodium transport in A6 cells. |
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Keywords: | asymmetric synthesis enzyme inhibition inositol lipid metabolic stability phosphatases sodium transport |
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