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A synthetic diphosphoinositol phosphate analogue of inositol trisphosphate

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Abstract

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)P2, the first diphosphate analogue of the intracellular signalling molecule InsP3, and examined its effects on InsP3 receptors, which are intracellular Ca2+ channels. 1-PP-Ins(4,5)P2 was indistinguishable from InsP3 in its ability to bind to and activate type 1 InsP3 receptors, indicating that the diphosphate modification of InsP3 affected neither affinity nor efficacy. Nevertheless, 1-PP-Ins(4,5)P2 is the most potent 1-phosphate modified analogue of InsP3 yet identified. PP-InsPs are generally hydrolysed by diphosphoinositol polyphosphate phosphohydrolases (DIPPs), but 1-PP-Ins(4,5)P2 was not readily metabolised by human DIPPs. Differential scanning fluorimetry showed that 1-PP-Ins(4,5)P2 stabilises DIPP proteins, but to a lesser extent than naturally occurring substrates 1-PP-InsP5 and 5-PP-InsP5. The non-hydrolysable InsP7 analogues 1-PCP-InsP5 and 5-PCP-InsP5 showed comparable stabilising abilities to their natural counterparts and may therefore be promising substrate analogues for co-crystallisation with DIPPs.

Graphical abstract: A synthetic diphosphoinositol phosphate analogue of inositol trisphosphate

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Publication details

The article was received on 16 Mar 2018, accepted on 01 May 2018 and first published on 04 Jun 2018


Article type: Research Article
DOI: 10.1039/C8MD00149A
Citation: Med. Chem. Commun., 2018, Advance Article
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    A synthetic diphosphoinositol phosphate analogue of inositol trisphosphate

    A. M. Riley, J. E. Unterlass, V. Konieczny, C. W. Taylor, T. Helleday and B. V. L. Potter, Med. Chem. Commun., 2018, Advance Article , DOI: 10.1039/C8MD00149A

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