Synthesis of an α-phosphono-α,α-difluoroacetamide Analogue of the Diphosphoinositol Pentakisphosphate 5-InsP

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2019 Aug 9

PMID 31391889

Citations 8

Authors

Andrew M Riley

Huanchen Wang

Stephen B Shears

Barry V L Potter

Affiliations

Soon will be listed here.

Abstract

Diphosphoinositol phosphates (PP-InsPs) are an evolutionarily ancient group of signalling molecules that are essential to cellular and organismal homeostasis. As the detailed mechanisms of PP-InsP signalling begin to emerge, synthetic analogues of PP-InsPs containing stabilised mimics of the labile diphosphate group can provide valuable investigational tools. We synthesised 5-PCFAm-InsP (), a novel fluorinated phosphonate analogue of 5-PP-InsP, and obtained an X-ray crystal structure of in complex with diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2). 5-PCFAm-InsP binds to the kinase domain of PPIP5K2 in a similar orientation to that of the natural substrate 5-PP-InsP and the PCFAm structure can mimic many aspects of the diphosphate group in 5-PP-InsP. We propose that , the structural and electronic properties of which are in some ways complementary to those of existing phosphonoacetate and methylenebisphosphonate analogues of 5-PP-InsP, may be a useful addition to the expanding array of chemical tools for the investigation of signalling by PP-InsPs. The PCFAm group may also deserve attention for wider application as a diphosphate mimic.

Citing Articles

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A structural exposé of noncanonical molecular reactivity within the protein tyrosine phosphatase WPD loop.

Wang H, Perera L, Jork N, Zong G, Riley A, Potter B Nat Commun. 2022; 13(1):2231.

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Multiple substrate recognition by yeast diadenosine and diphosphoinositol polyphosphate phosphohydrolase through phosphate clamping.

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Chin A, Gao Z, Riley A, Furkert D, Wittwer C, Dutta A Sci Adv. 2020; 6(44).

PMID: 33115740 PMC: 7608788. DOI: 10.1126/sciadv.abb8542.

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