title: Elucidating diphosphoinositol polyphosphate function with nonhydrolyzable analogues.
abstract: 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-IP5 and 5PCP-IP5 inhibited Akt phosphorylation with similar potencies, 1PCP-IP5 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.
authors.affiliation: Department of Chemistry, Princeton University, Washington Rd, Princeton, NJ 08544 (USA).
authors.forename: Mingxuan
authors.initials: M
authors.lastname: Wu
authors.forename: Lucy S
authors.initials: LS
authors.lastname: Chong
authors.forename: Samanta
authors.initials: S
authors.lastname: Capolicchio
authors.forename: Henning J
authors.initials: HJ
authors.lastname: Jessen
authors.forename: Adam C
authors.initials: AC
authors.lastname: Resnick
authors.forename: Dorothea
authors.initials: D
authors.lastname: Fiedler
mesh_terms: D006868:Hydrolysis; D008958:Models, Molecular; D010716:Phosphatidylinositols / Q000737:chemistry*; D010766:Phosphorylation; D011122:Polyphosphates / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D010716:Phosphatidylinositols; D011122:Polyphosphates
keywords: diphosphoinositol polyphosphate; mechanistic probe; nonhydrolyzable analogues; phosphorylation; second messengers