Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs. Issue 32 (28th July 2021)

• Record Type: Journal Article
• Authors: Hostachy, Sarah; Utesch, Tillmann; Franke, Katy; Dornan, Gillian Leigh; Furkert, David; Türkaydin, Berke; Haucke, Volker; Sun, Han; Fiedler, Dorothea
• Is Part Of: Chemical science. Volume 12:Issue 32(2021)
• Page Start: 10696
• Page End: 10702
• Publication Date: 2021-07-28
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc02975d
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : 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. 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.