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Elucidating Diphosphoinositol Polyphosphate Function with Nonhydrolyzable Analogues
Author(s) -
Wu Mingxuan,
Chong Lucy S.,
Capolicchio Samanta,
Jessen Henning J.,
Resnick Adam C.,
Fiedler Dorothea
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201402905
Subject(s) - allosteric regulation , second messenger system , phosphorylation , phosphatase , polyphosphate , chemistry , biochemistry , signal transduction , function (biology) , sugar phosphates , microbiology and biotechnology , biology , phosphate , enzyme
The diphosphoinositol polyphosphates (PP‐IPs) represent a novel class of high‐energy phosphate‐containing messengers which control a wide variety of cellular processes. It is thought that PP‐IPs exert their pleiotropic effects as allosteric regulators and through pyrophosphorylation of protein substrates. However, most details of PP‐IP signaling have remained elusive because of a paucity of suitable tools. We describe the synthesis of PP‐IP bisphosphonate analogues (PCP‐IPs), which are resistant to chemical and biochemical degradation. While the two regioisomers 1PCP‐IP 5 and 5PCP‐IP 5 inhibited Akt phosphorylation with similar potencies, 1PCP‐IP 5 was much more effective at inhibiting its cognate phosphatase hDIPP1. Furthermore, the PCP analogues inhibit protein pyrophosphorylation because of their inability to transfer the β‐phosphoryl group, and thus enable the distinction between PP‐IP signaling mechanisms. As such, the PCP analogues will find widespread applications for the structural and biochemical characterization of PP‐IP signaling properties.