Chemistry

Document Type

Article

Abstract

Insulin-degrading enzyme (IDE) is a zinc metalloprotease that selectively degrades biologically important substrates associated with type 2 diabetes and Alzheimer's disease (AD). As such, IDE is an attractive target for therapeutic innovations. Amajor requirement is an understanding of how other molecules present in cells regulate the activity of the enzyme toward insulin, IDE's most important physiologically relevant substrate. Previous kinetic studies of the IDE-dependent degradation of insulin in the presence of potential regulators have used iodinated insulin, a chemical modification that has been shown to alter the biological and biochemical properties of insulin. Here, we present a novel kinetic assay that takes advantage of the loss of helical circular dichroic signals of insulin with IDE-dependent degradation. As proof of concept, the resulting Michaelis-Menten kinetic constants accurately predict the known regulation of IDE by adenosine triphosphate (ATP). Intriguingly, we found that when Mg2+ is present with ATP, the regulation is abolished. The implication of this result for the development of preventative and therapeutic strategies for AD is discussed. We anticipate that the new assay presented here will lead to the identification of other small molecules that regulate the activity of IDE toward insulin.

Publication Title

Bioscience Reports

Publication Date

11-7-2018

Volume

38

Issue

6

ISSN

0144-8463

DOI

10.1042/BSR20181416

Cross Post Location

Student Publications

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Included in

Chemistry Commons

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