Centre for Research on Biomolecular Interactions presents Assoc. Prof. James L. Hougland, Department of Chemistry, Syracuse University, Syracuse, USA

Talk Title: "Hungry like the GOAT: The unique biochemistry and biology of ghrelin"

Abstract: Ghrelin is a peptide hormone involved in appetite stimulation, energy balance regulation, glucose homeostasis, and a range of other physiological and neurological pathways. Ghrelin requires octanoylation of a serine side chain, a unique posttranslational modification within the human proteome, to bind its cognate receptor and activate signaling. The enzyme that catalyzes this acylation, ghrelin O-acyltransferase (GOAT), was identified in 2008 as a member of the membrane-bound O-acyltransferase (MBOAT) enzyme superfamily. Ghrelin is the only predicted substrate for GOAT, suggesting that blocking ghrelin acylation using GOAT inhibitors potentially offers a specific and targeted therapeutic avenue to treat conditions impacted by ghrelin signaling. We are applying chemical, biochemical, and computational approaches to investigate ghrelin acylation by human GOAT (hGOAT). Using structure-activity analysis of substrates and inhibitors, we’ve identified multiple functional groups within ghrelin recognized by hGOAT. Small molecule hGOAT inhibitors have revealed hGOAT contains a functionally essential cysteine residue, providing a chemical avenue for locating domains within hGOAT required for enzyme activity. Defining the hGOAT active site and substrate binding sites through computational and biochemical analyses offers insight into the structure of this integral membrane acyltransferase and related enzymes while providing guidance for designing and optimizing hGOAT inhibitors.

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