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Repositioning of Ritanserin for the Inhibition of DGK-Alpha and the Role of the Polybasic Domain in the Phosphoregulation of Lipins 1 and 3

Boroda, Salome
Format
Thesis/Dissertation; Online
Author
Boroda, Salome
Advisor
Harris, Thurl
Abstract
The diversity and multi-functionality of cellular lipids is astounding. At the hub of phospho- and neutral lipid flux are two lipids with many effector proteins: diacylglycerol (DAG) and phosphatidic acid (PA). Enzymes which can simultaneously regulate both of their levels are diacylglycerol kinases (DGKs) and lipins. The former phosphorylates DAG to yield PA and the latter dephosphorylates PA to generate DAG. The work herein approaches the study of DGKs and lipins from two different perspectives. First, we have built upon previous work, which established DGKα as a therapeutic target in glioblastoma multiforme (GBM), and have repositioned ritanserin, a serotonin receptor (5-HTR) antagonist, as a pharmacological tool for attenuating DGK activity. We have also elucidated the polypharmacology of other DGK inhibitors, and shown that they are potent 5-HTR antagonists. Second, we hypothesized that the varying PA-binding domains, or polybasic domains (PBDs), of each lipin are involved in the phosphoregulatory differences among these enzymes. We show, for the first time, that insertion of the lipin 3 PBD in the lipin 1 enzyme eliminates the phosphoregulation of lipin 1. Conversely, the insertion of lipin 1 PBD into the lipin 3 protein allows phosphorylated residues on lipin 3 to negatively regulate its activity in vitro. These data suggest that the differences in the amino acid sequence between PBDs of these two proteins are sufficient to determine whether or not the enzymes can be controlled by intramolecular phosphoregulation
Language
English
Published
University of Virginia, Department of Pharmacology, PHD (Doctor of Philosophy), 2017
Published Date
2017-04-28
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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