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Title page for ETD etd-06232006-122911

Type of Document Dissertation
Author Thompson, Lawrence Casper
Author's Email Address larry.thompson@vanderbilt.edu
URN etd-06232006-122911
Title Dynamic, Structural, and Mechanistic Study of Glutathione Transferases
Degree PhD
Department Biochemistry
Advisory Committee
Advisor Name Title
Richard N Armstrong Committee Chair
Albert H Beth Committee Member
Charles R Sanders Committee Member
Lawrence J Marnett Committee Member
Michael R Waterman Committee Member
  • hcca isomerase
  • hydrogen-deuterium exchange mass spectrometry
  • glutathione cofactor
  • isomerization
  • glutathione binding
  • mechanistic enzymology
  • transient state kinetics
  • crystallography
  • naphthalene metabolism
  • Xenobiotics -- Metabolism
  • phase II enzymes
  • xenobiotic catabolism
  • kappa glutathione transferases
  • dimer stability
  • Glutathione transferase
Date of Defense 2006-06-15
Availability unrestricted
This project involved the investigation of both the dynamic features of the dimer interface of the Mu class GSH transferase rGSTM1-1, as well as, the structural and mechanistic characteristics of HCCA Isomerase, an enzyme related to the mitochondrial (Kappa) GSH transferase family. The dynamics along the dimer interface of rGSTM1-1 were probed by using site-directed mutagenesis and hydrogen-deuterium exchange mass spectrometry. This work led to hypotheses about the roles of both hydrophobic and electrostatic motifs along the interface. It also resulted in more clear understanding of the regions within each monomer that are important for the stability of individual subunits. Crystallography of HCCA Isomerase in conjunction with activity assays on the native substrates allowed us to conclude that this enzyme is definitely a Kappa GSH transferase. Transient state kinetic measurements with native substrates and analogs as well as crystallography with one of the analogs allowed us to propose a global pathway for HCCA Isomerase’s catalytic mechanism.

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