Document Detail


5-Stabilized phosphatidylinositol 3,4,5-trisphosphate analogues bind Grp1 PH, inhibit phosphoinositide phosphatases, and block neutrophil migration.
MedLine Citation:
PMID:  20052709     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Honglu Zhang; Ju He; Tatiana G Kutateladze; Takahiro Sakai; Takehiko Sasaki; Nicolas Markadieu; Christophe Erneux; Glenn D Prestwich
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chembiochem : a European journal of chemical biology     Volume:  11     ISSN:  1439-7633     ISO Abbreviation:  Chembiochem     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-15     Completed Date:  2010-05-04     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  100937360     Medline TA:  Chembiochem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  388-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Cell Movement / drug effects*
Humans
Mice
Neutrophils / cytology,  drug effects*,  immunology
PTEN Phosphohydrolase / antagonists & inhibitors,  metabolism
Phosphatidylinositol Phosphates / chemistry*,  metabolism,  pharmacology
Phosphoric Monoester Hydrolases / antagonists & inhibitors,  metabolism*
Protein Binding
Protein Structure, Tertiary
Receptors, Cytoplasmic and Nuclear / metabolism*
Xenopus laevis
Grant Support
ID/Acronym/Agency:
GM 071424/GM/NIGMS NIH HHS; NS 29632/NS/NINDS NIH HHS; R01 GM071424/GM/NIGMS NIH HHS; R01 GM071424-01A2/GM/NIGMS NIH HHS; R01 NS029632-09/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Phosphatidylinositol Phosphates; 0/Receptors, Cytoplasmic and Nuclear; 0/phosphatidylinositol 3,4,5-triphosphate; 0/phosphatidylinositol receptors; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.56/inositol-1,4,5-trisphosphate 5-phosphatase; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections

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