Date of Award
Doctor of Philosophy (PhD)
David W. Christianson
The arginase-deacetylase family of enzymes has been extensively studied in recent years due to the overwhelming medicinal applications of these enzymes. One member of this family, histone deacetylases, is emerging as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. While four FDA approved histone deacetylase inhibitors currently exist, including Vorinostat, Belinostat, Panobinostat, and Romidepsin, these inhibitors are nonspecific. Consequently, multiple histone deacetylases are targeted, resulting in various off-target effects and cytotoxicity buildup. Rationally designing selective inhibitors will improve pharmacokinetic properties that are desired for clinical applications, however, this has proven to be a nontrivial task. Many members of the arginase-deacetylase family remain uncharacterized in terms of both structure and function, adding another layer of complexity to the matter. Here, this thesis describes the characterization of several enzymes in the arginase-deacetylase family including the second catalytic domain of histone deacetylase 6 (HDAC6 CD2), the first catalytic domain of histone deacetylase 6 (HDAC6 CD1), and acetylpolyamine amidohydrolase from Marinobacter subterrani (msAPAH). Through a series of inhibitor affinity measurements, enzyme kinetics, and structural evaluation, these studies provide a foundation for designing selective histone deacetylase inhibitors with safer therapeutic properties as well as provide new insight into understanding the arginase-deacetylase family of enzymes.
Osko, Jeremy Daniel, "Structural Aspects Of Selective Inhibitor Binding To Histone Deacetylase 6 And Related Deacetylases" (2020). Publicly Accessible Penn Dissertations. 3764.