The Role of Cobalamin in Biological Photochemistry Public Deposited

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  • March 19, 2019
Creator
  • Smith, Weston
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • This dissertation is divided into two parts. The first part describes the development of small molecule drug delivery systems that exploit human erythrocytes as drug carriers and photolabile cobalamin-drug complexes as light activated “switches”. These complexes are activated by energy transfers from long wavelength fluorophores that act as antennae receptive to wavelengths of light that reside in the optical window of tissue. The first of these delivery systems takes advantage of hydrophobic anchors to bind fluorescent antennae and cobalamin complexes to the exterior of erythrocyte membranes and allows the two to interact by free association. The second of these systems appends the fluorophores directly to the cobalamin-drug complexes and these delivery units are loaded to the interior of the red blood cell through hypotonic pore formation. Upon irradiation, these red blood cells release chemotherapeutics. The second half of this dissertation describes cobalamin complexes designed for the study of cellular signal transduction. First, a peptide substrate for the proto-oncogene tyrosine kinase Src is complexed with a cobalamin based membrane anchor, sequestering it inside of the glycocalyx of erythrocyte ghosts. Photoactivation of the substrate with green light allows the substrate to diffuse away from the membrane allowing phosphorylation by Src. This proof of concept demonstrates that membrane sequestration could be a viable means of sampling endogenous kinase activity in intracellular environments. The second cobalamin based signaling tool is a “caged” cAMP dependent protein kinase that is inactive until illuminated with ≤ 577 nm light. Such enzymes have been used in the past to study the effect of targeted bursts of enzyme activity in living cells. We hope that our light activated enzyme will lead to technologies that allow multiple enzymes to be controlled in sequential order.
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  • In Copyright
Advisor
  • Waters, Marcey
  • Spremulli, Linda
  • Sims, Christopher
  • Gagne, Michel
  • Lawrence, David
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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