Abstract
The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.
Highlights
Based on the failure of Edman degradation to identify the serine residue at the third position (Ser-3) and the lack of biological activity exhibited by synthetic ghrelin, Kojima and co-workers hypothesized that this residue undergoes a functionally essential posttranslational modification to produce active ghrelin
The receptor contains three conserved residues Glu140-Arg141-Tyr142 located at the intracellular end of transmembrane helix 3 (TM 3) which are critical for the isomerization of the receptor between its active and inactive conformations
Both variants are expressed in brain regions including the hypothalamus, hippocampus, amygdala, mesencephalic dopaminergic regions and striatum, with GHS-R1a recognized as the functional ghrelin receptor [47,49]
Summary
Ghrelin was first observed to be responsible for the regulation of nutrient sensing, meal initiation and appetite, giving ghrelin its most well-known nickname as the ‘hunger hormone’ [8,9]. Ghrelin exerts its influence on multiple physiological pathways beyond its original linkage to growth hormone secretion and appetite regulation (figure 1) [9]. These pathways include glucose metabolism and energy homeostasis [10,11,12,13,14,15], organismal response to starvation [16,17,18,19], cardio-protection [20,21], protection against muscle atrophy [22,23,24] and bone metabolism [9,25]. Due to this wide range of physiological signalling functions, the ghrelin signalling pathway and its associated proteins are considered attractive unexploited targets for therapeutic development and clinical application [39]
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