Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs

Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are densely phosphorylated eukaryotic messengers, which are involved in numerous cellular processes. To elucidate their signaling functions at the molecular level, non-hydrolyzable bisphosphonate analogs of inositol pyrophosphates, PCP-InsPs, ha...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2021-08, Vol.12 (32), p.1696-172
Main Authors: Hostachy, Sarah, Utesch, Tillmann, Franke, Katy, Dornan, Gillian Leigh, Furkert, David, Türkaydin, Berke, Haucke, Volker, Sun, Han, Fiedler, Dorothea
Format: Article
Language:English
Subjects:
Analogs
Binding sites
Bisphosphonates
Chemistry
Enzymes
Insulin
Metabolites
Molecular docking
Molecular dynamics
Phosphate esters
Reagents
Substrates
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Summary:Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are densely phosphorylated eukaryotic messengers, which are involved in numerous cellular processes. To elucidate their signaling functions at the molecular level, non-hydrolyzable bisphosphonate analogs of inositol pyrophosphates, PCP-InsPs, have been instrumental. Here, an efficient synthetic strategy to obtain these analogs in unprecedented quantities is described - relying on the use of combined phosphate ester-phosphoramidite reagents. The PCP-analogs, alongside their natural counterparts, were applied to investigate their regulatory effect on insulin-degrading enzyme (IDE), using a range of biochemical, biophysical and computational methods. A unique interplay between IDE, its substrates and the PP-InsPs was uncovered, in which the PP-InsPs differentially modulated the activity of the enzyme towards short peptide substrates. Aided by molecular docking and molecular dynamics simulations, a flexible binding mode for the InsPs/PP-InsPs was identified at the anion binding site of IDE. Targeting IDE for therapeutic purposes should thus take regulation by endogenous PP-InsP metabolites into account. An efficient synthesis of non-hydrolyzable inositol pyrophosphate analogs was developed to subsequently investigate the regulation of insulin-degrading enzyme by these hyperphosphorylated signaling molecules.
ISSN:2041-6520
2041-6539
DOI:10.1039/d1sc02975d