Ghrelin is a hormone involved in appetite stimulation, glucose metabolism, and a range of neurological pathways including those associated with addictive behaviors. Ghrelin requires serine octanoylation, a unique posttranslational modification, to bind its receptor and activate signaling. The enzyme catalyzing this acylation, ghrelin O-acyltransferase (GOAT), is a protein-modifying member of the membrane-bound O-acyltransferase (MBOAT) enzyme superfamily. Ghrelin is the only substrate for GOAT, offering an avenue for specific modulation of ghrelin signaling through GOAT inhibition. Blocking ghrelin acylation potentially offers a targeted therapeutic avenue to treat health conditions impacted by ghrelin signaling such as diabetes, obesity, and addictive behaviors. We are applying chemical, biochemical, and computational approaches to investigate ghrelin acylation by human GOAT (hGOAT) and roles played by GOAT in cellular function. Defining the hGOAT active site and substrate binding sites through computational and biochemical analyses has provided insight into the structure and mechanism of this integral membrane acyltransferase and related enzymes. Creation of GOAT-specific ligands has identified molecular determinants for ghrelin recognition between GOAT and the ghrelin receptor. These ligands have also enabled investigation of unanticipated roles of GOAT in ghrelin signaling and cell biology – for example, cell-based studies suggest GOAT shows promise as a cancer biomarker. Moving beyond the view of ghrelin as the “hunger hormone,” our work provides a molecular foundation for understanding the multiple roles this secreted peptide plays within the body. This understanding will then guide exploitation of therapeutic options for targeting GOAT in disease treatment.

How a peptide hormone GOAT acylated: The chemistry, biology, and endocrinology of ghrelin O-acyltransferase

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ACS Fall 2022

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