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Title page for ETD etd-10012014-134811


Type of Document Dissertation
Author Kramer, Glenna Jean
URN etd-10012014-134811
Title Pharmacology and Chemical Probe Development of the K-26 Family of Natural Product Angiotensin-I Converting Enzyme Inhibitors
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Brian O. Bachmann Committee Chair
D. Bordon Lacy Committee Member
Gary A. Sulikowski Committee Member
Lawrence Marnett Committee Member
Keywords
  • natural product
  • Angiotensin I converting enzyme
  • bacterial dicarboxypeptidase
  • ACE inhibitor
  • K-26
Date of Defense 2014-09-29
Availability unrestricted
Abstract
K-26 and related (R)-AHEP containing natural products have been described as some of the most potent natural product inhibitors of human angiotensin-I converting enzyme (ACE) a physiologically important enzyme central to blood pressure regulation in mammals. Despite the pharmacological relevance of this family of natural products, structural activity relationship studies have been limited and many questions remain unanswered regarding the biosynthesis and target of this metabolite. Herein we describe the pharmacology of K-26 and other related (R)-AHEP containing natural products with both mammalian and bacterial ACE. We also apply the computational tool Rosetta in structural activity relationship studies on a set of 400 K-26 variants to identify potential variants with domain selective or potent inhibitory properties and experimentally validate the predictions. Furthermore, K-26 is developed into a solid-phase chemical probe capable of capturing human ACE with potential future applications in both target and biosynthetic enzyme identification.
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