• Login
    View Item 
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    •   Home
    • UA Graduate and Undergraduate Research
    • UA Theses and Dissertations
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UA Campus RepositoryCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournalThis CollectionTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournal

    My Account

    LoginRegister

    About

    AboutUA Faculty PublicationsUA DissertationsUA Master's ThesesUA Honors ThesesUA PressUA YearbooksUA CatalogsUA Libraries

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Search for bioactive conformation of glucagon and development of potent glucagon antagonists

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    azu_td_9992136_sip1_m.pdf
    Size:
    4.658Mb
    Format:
    PDF
    Download
    Author
    Ahn, Jung-Mo
    Issue Date
    2000
    Keywords
    Chemistry, Organic.
    Advisor
    Hruby, Victor J.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    In pursuit of the working model of how glucagon interacts with the glucagon receptor and how glucagon antagonists exert their different activities, 42 glucagon analogues were designed and synthesized. An attempt to determine the minimum sequence for binding affinity of glucagon analogues was carried out and resulted in several potent truncated glucagon antagonists with substantial binding affinity, such as phenylbutyryl-glucagon(10-29) amide. Furthermore, a new method for determining the bioactive conformations of peptide hormones has been designed. In a positional cyclization scanning study, several conformationally constrained glucagon analogues containing disulfide or lactam bridges were synthesized, and the biological assay results showed that the alpha-helical conformation is required for the maximal receptor recognition. This study resulted in two superpotent glucagon analogues, c[Lys⁵, Glu⁹]glucagon amide and c[Lys¹⁷, Glu²¹]glucagon amide, which have picomolar binding affinities. A structure-activity relationship study of glycine at position 4 was performed to determine the importance of flexibility in the N-terminal region of glucagon. Four glucagon analogues were designed and synthesized, and all showed extremely potent antagonistic activity with improved binding affinity. Also, the potent glucagon antagonist [desHis¹, desPhe⁶, Glu⁹] glucagon amide was synthesized on a large scale (ca. 1.5 g), and the effect of the glucagon antagonist on diabetic ketoacidosis was studied in vivo in alloxan-induced diabetic dogs. The glucagon antagonist clearly showed its effectiveness in controlling serum bicarbonate concentration, while the control experiment with saline demonstrated increased diabetic ketoacidosis. This study clearly showed the possibility of using glucagon antagonists as therapeutic agents for the treatment of diabetic ketoacidosis. The conformation of the potent glucagon antagonist [desHis¹, desPhe⁶, Glu⁹] glucagon amide was studied using 2D NMR spectroscopy, and deuterated dodecylphosphocholine micelles were utilized to imitate the membrane environment. In this investigation, TOCSY, DQF-COSY, and NOESY spectra of the glucagon antagonist in a deuterated DPC micelle solution were acquired at pH 6.0 and 37°C. Restrained molecular dynamics (simulated annealing) using 332 distance restraints and 16 torsion angle restraints resulted in a conformation which displayed a similar C-terminal conformation, but a distinctly different N-terminal region, as compared to the conformation of glucagon. The newly discovered salt bridge between Ser² and Glu⁹ presumably resulted from the increased flexibility of the N-terminal region by the deletion of Phe⁶ and substitution of Glu⁹, which may shed light on how small changes in the sequence of peptides can significantly modify the conformation.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Chemistry
    Degree Grantor
    University of Arizona
    Collections
    Dissertations

    entitlement

     
    The University of Arizona Libraries | 1510 E. University Blvd. | Tucson, AZ 85721-0055
    Tel 520-621-6442 | repository@u.library.arizona.edu
    DSpace software copyright © 2002-2017  DuraSpace
    Quick Guide | Contact Us | Send Feedback
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.