Characterization of Ghrelin as a Novel Insulin-Degrading Enzyme Substrate

Date of Award

2019

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Benjamin J. Alper, Ph.D.

Abstract

Insulin-degrading enzyme (IDE) is zinc metalloprotease able to hydrolyze many small to intermediate peptides and plays a critical role in glucose homeostasis throughout the human body. This is done through the regulation of one of IDE's primary substrates, insulin. IDE however has been characterized to play many roles throughout the body and has been the target of study for many different areas of science. As well as playing a main role in degrading insulin, IDE has also found to degrade other varying peptides ranging from related peptides such as glucagon, to in more recent studies amylin as well as amyloid beta. This variety of substrates makes the study of IDE fascinating and critical when looking to treat diseases such as diabetes, to even possibly looking at IDE as a possible way to treat Alzheimer's disease through its degradation of amyloid beta and regulation of aggregate plaque buildup. Here, a novel substrate of IDE has been expressed and characterized through extensive SDS-PAGE analysis as well as the development of several kinetic assays. Through this research, the hunger hormone known as ghrelin has shown to be cleaved by IDE under several repeatable conditions. Ghrelin plays critical roles in hunger regulation, growth hormone release, and energy metabolism. This intriguing new substrate of IDE has also been found to have a specified relationship with IDE's enzymatic activity and seems to have at least some specificity to IDE in order to be degraded. In total four varying enzymes known to cleave specific similar substrates were all examined in this study with only IDE displaying a degrading potential against ghrelin. This proposed new substrate could prove most interesting in providing more insight to the regulatory role IDE plays throughout the human body in regulating glucose levels, to now also playing a proposed role in hunger signaling and energetic metabolic rates.

Comments

Master's thesis submitted to the faculty of Sacred Heart University's Chemistry Program in partial fulfillment of the requirements for the degree of Master of Chemistry.

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