Figure 1.

(A) GOAT-catalyzed octanoylation of pro-ghrelin is a critical part of ghrelin maturation. GOAT is weakly inhibited by its reaction product, acyl ghrelin (1), and more potently by analog 2, wherein Ser-3 is replaced by diaminopropionic acid (DAP). Systemic inhibition of GOAT is expected to reduce circulating acyl-ghrelin levels, leading to improved insulin response to glucose challenge. (B) GOAT inhibition can be achieved by targeting either the substrate or co-substrate site, or by targeting both sites with a “bisubstrate” mimic. (C–E) Known inhibitors of GOAT.