Details

Autor(en) / Beteiligte

• Riley, Andrew M
• Unterlass, Judith E
• Konieczny, Vera
• Taylor, Colin W
• Helleday, Thomas
• Potter, Barry V. L

Titel

A synthetic diphosphoinositol phosphate analogue of inositol trisphosphateElectronic supplementary information (ESI) available: NMR spectra, additional DSF data and details of molecular docking experiments. See DOI: 10.1039/c8md00149a

Erscheinungsjahr

2018-07

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Diphosphoinositol phosphates (PP-InsPs) are inositol phosphates (InsPs) that contain PP (diphosphate) groups. Converting a phosphate group in an InsP into a diphosphate has been reported to enhance affinity for some binding proteins. We synthesised 1-PP-Ins(4,5)P 2 , the first diphosphate analogue of the intracellular signalling molecule InsP 3 , and examined its effects on InsP 3 receptors, which are intracellular Ca 2+ channels. 1-PP-Ins(4,5)P 2 was indistinguishable from InsP 3 in its ability to bind to and activate type 1 InsP 3 receptors, indicating that the diphosphate modification of InsP 3 affected neither affinity nor efficacy. Nevertheless, 1-PP-Ins(4,5)P 2 is the most potent 1-phosphate modified analogue of InsP 3 yet identified. PP-InsPs are generally hydrolysed by diphosphoinositol polyphosphate phosphohydrolases (DIPPs), but 1-PP-Ins(4,5)P 2 was not readily metabolised by human DIPPs. Differential scanning fluorimetry showed that 1-PP-Ins(4,5)P 2 stabilises DIPP proteins, but to a lesser extent than naturally occurring substrates 1-PP-InsP 5 and 5-PP-InsP 5 . The non-hydrolysable InsP 7 analogues 1-PCP-InsP 5 and 5-PCP-InsP 5 showed comparable stabilising abilities to their natural counterparts and may therefore be promising substrate analogues for co-crystallisation with DIPPs. We describe the synthesis and biological evaluation of 1-PP-Ins(4,5)P 2 , the first diphosphate-containing analogue of the intracellular signalling molecule Ins(1,4,5)P 3 .