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GIOLITO, Maria Luz

CONICET PhD fellow
Director: Javier Valdez Taubas

PhD Thesis Topic

Isolation and characterization of palmitoyltransferases inhibitors
S-acylation or palmitoylation consists in the addition of fatty acids on cysteine residues and is performed by a family of enzymes called palmitoyltransferases (PATs), which are responsible for almost every palmitoylation event so far described. It participates in the regulation of many biologically important processes such as signal transduction and synaptic transmission. Mutations in PATs have been associated with mental retardation, schizophrenia and other mental disorders. This is why there is great interest in obtaining specific inhibitors of S-acylation. My working plan focalizes in: generating yeast screening assays that allow the isolation of heterologously expressed PATs-specific inhibitors. These assays are based on a system of reporter genes which respond to the acylation status of a palmitoylation substrate which is fused to a transcription factor. The inhibitory molecules we will test are cyclic peptides encoded in a plasmid library. Initially we will focus on palmitoyltransferase DHHC9, which palmitoylates the oncoprotein Ras and is necessary for its transforming activity. Additionally, we propose to search for inhibitors of the PAT DHHC20 which palmitoylates the epidermal growth factor receptor (EGFR), being the final purpose to characterize the effectiveness of the inhibitors and to explore its utilization as therapeutic agents.