Abstract
Ghrelin is a 28-residue peptide hormone produced by stomach P/D1 cells located in oxyntic glands of the fundus mucosa. Post-translational octanoylation of its Ser-3 residue, catalyzed by MBOAT4 (aka ghrelin O-acyl transferase (GOAT)), is essential for the binding of the hormone to its receptor in target tissues. Physiological roles of acyl ghrelin include the regulation of food intake, growth hormone secretion from the pituitary, and inhibition of insulin secretion from the pancreas. Here, we describe a medicinal chemistry campaign that led to the identification of small lipopeptidomimetics that inhibit GOAT in vitro. These molecules compete directly for substrate binding. We further describe the synthesis of heterocyclic inhibitors that compete at the acyl coenzyme A binding site.
Highlights
Ghrelin is a 28-residue lipopeptide (Figure 1A) discovered by Kojima and co-workers as the endogenous ligand for the growth hormone secretagogue receptor (GHS-r) [1]
In 2008, Yang et al utilized a candidate cloning approach to demonstrate that membrane-bound O-acyl transferase (MBOAT) 4, termed ghrelin O-acyl transferase (GOAT), the only MBOAT capable of catalyzing proghrelin octanoylation [2]
MS/MS fragmentation analyses of GOAT acylated ghrelin showed that the acylation is on serine-3, identical to acyl ghrelin produced in the stomach
Summary
Ghrelin is a 28-residue lipopeptide (Figure 1A) discovered by Kojima and co-workers as the endogenous ligand for the growth hormone secretagogue receptor (GHS-r) [1]. Yang hypothesized this atypical lipidation was likely performed by a member of the membrane-bound O-acyl transferase (MBOAT) family of enzymes [2]. The MBOATs catalyze the lipidation of a variety of substrates including phospholipids, neutral lipids, and proteins using saturated and unsaturated acyl coenzyme-A derivatives as acyl donors [3]. In 2008, Yang et al utilized a candidate cloning approach to demonstrate that MBOAT 4, termed ghrelin O-acyl transferase (GOAT), the only MBOAT capable of catalyzing proghrelin octanoylation [2]. Gutierrez used a candidate gene silencing approach to independently reach the same conclusion for human GOAT [4]. Short-interfering RNAs (siRNAs) were produced and the effects of silencing individual MBOAT genes were observed. MS/MS fragmentation analyses of GOAT acylated ghrelin showed that the acylation is on serine-3, identical to acyl ghrelin produced in the stomach
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