STRUCTURAL BASIS OF SUBSTRATE RECOGNITION IN THIMET OLIGOPEPTIDASE AND DEVELOPMENT OF NANOPARTICLES FOR THERAPEUTIC ENZYME DELIVERY
Year of Publication
Doctor of Philosophy (PhD)
Dr. David Rodgers
Dr. Bruce Hinds
Neuropeptidases are responsible for degradation of signaling peptides in the central nervous system and periphery. Some neuropeptidases have also been shown to play a role as part of the cell’s hydrolytic machinery responsible for breaking down proteins and peptides into amino acids, and these enzymes therefore influence small peptide availability for antigen presentation. A better understanding of how neuropeptidases recognize their substrates could lead to therapeutics that modulate the activity of these important enzymes. Alternatively, re-engineering these enzymes to selectively hydrolyze undesirable peptides could make them attractive as therapeutics themselves. A key question in understanding the activity of these enzymes is how they are able to recognize a variety of seemingly unrelated amino acid sequences as cleavage sites. We are investigating the basis for this general substrate recognition in neuropeptidases using thimet oligopeptidase (TOP) as a model. Crystal structures of TOP in complex with a variety of substrates and inhibitors shed light on the mechanisms underlying substrate recognition and pave the way for re-targeting substrate recognition in these enzymes.
Nano test tube particles have been proposed as a means of delivering therapeutics such as enzymes. However, the template synthesis method for nano test tube production does not produce therapeutic quantities. In order to take full advantage of re-engineered neuropeptidases a new method for nano test tube synthesis has been developed. We show that a non-destructive template synthesis methodology can be applied to produce nano test tube particles in quantities useful for therapeutic enzyme immobilization.
Wagner, Jonathan Mark, "STRUCTURAL BASIS OF SUBSTRATE RECOGNITION IN THIMET OLIGOPEPTIDASE AND DEVELOPMENT OF NANOPARTICLES FOR THERAPEUTIC ENZYME DELIVERY" (2012). Theses and Dissertations--Molecular and Cellular Biochemistry. 6.
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