Ghrelin is a peptide hormone involved in appetite stimulation, regulation of glucose homeostasis, and a range of other physiological processes. Ghrelin requires a unique posttranslational modification, octanoylation of a serine side chain, to bind its cognate receptor and activate signaling. The enzyme that catalyzes this modification, ghrelin O-acyltransferase (GOAT), is receiving increased interest as a potential drug target for treatment of obesity, diabetes, and other diseases potentially linked to ghrelin signaling. As ghrelin is the only known substrate of GOAT, blocking ghrelin acylation using GOAT inhibitors potentially offers a specific and targeted avenue to treat health conditions impacted by ghrelin signaling. Several classes of GOAT inhibitors have been reported, but designing novel potent GOAT inhibitors will be significantly aided by a molecular-scale model of the interactions between ghrelin and the GOAT active site. Our research focuses on understanding the substrate specificity and catalytic mechanism of GOAT.  We have expressed the human form of GOAT (hGOAT) and demonstrated its octanoylation activity using a fluorescent peptide substrate that mimics the N-terminal sequence of ghrelin.  Through structure-reactivity analysis of a series of peptide substrates, we have identified multiple functional groups within ghrelin required for recognition and subsequent modification by hGOAT.  We have also developed a synthetic approach that allows rapid creation of a diverse panel of lipid-containing inhibitors to potentially access novel GOAT inhibitors with increased potency and bioavailability.  Defining the interactions used by hGOAT to bind, recognize, and acylate ghrelin will provide insight into the structure of the hGOAT active site, guide the design of targeted hGOAT inhibitors, and aid in identifying potential novel hGOAT substrates.

Ghrelin acylation by human ghrelin <i>O</i>-acyltransferase: Substrate selectivity, mechanism, and inhibitor development

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Ghrelin acylation by human ghrelin O-acyltransferase: Substrate selectivity, mechanism, and inhibitor development