Issue 32, 2021

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

Abstract

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
01 জুন 2021
Accepted
06 জুলাই 2021
First published
08 জুলাই 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 10696-10702

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

S. Hostachy, T. Utesch, K. Franke, G. L. Dornan, D. Furkert, B. Türkaydin, V. Haucke, H. Sun and D. Fiedler, Chem. Sci., 2021, 12, 10696 DOI: 10.1039/D1SC02975D

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