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Review
. 2021 Jul;11(7):210080.
doi: 10.1098/rsob.210080. Epub 2021 Jul 28.

Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling

Tasha R Davis  1 , Mariah R Pierce  1 , Sadie X Novak  1 , James L Hougland  1   2
Affiliations
Review

Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling

Tasha R Davis et al. Open Biol. 2021 Jul.

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.

Keywords: GHS-R1a; ghrelin; ghrelin O-acyltransferase; membrane-bound O-acyltransferase; neuroendocrinology; protein acylation.

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Figures

Figure 1.
Figure 1.
Ghrelin signalling impacts a wide range of physiological pathways. Ghrelin is involved in a multitude of pathways including appetite stimulation, glucose homeostasis, adipogenesis, cardiovascular health and modulation of addictive behaviour. Figure created with BioRender.com.
Figure 2.
Figure 2.
GHS-R1a structure reveals a proposed binding for ghrelin. The binding site for ghrelin is composed of two regions on the receptor extracellular face, with polar contact to amino acids for contacts with the ghrelin N-terminal amino acids and a nonpolar surface for interaction with the octanoyl group attached through the serine ester. Figure created in PyMol using PDB 6KO5.
Figure 3.
Figure 3.
MBOAT family acyltransferases with protein substrates. GOAT, Hhat and PORCN catalyse acylation of their respective substrates (ghrelin, Hedgehog and Wnt) as these proteins proceed through the ER on the secretion pathway. Figure created with BioRender.com and PyMOL using PDB files 6RVD (Hedgehog), 6H3E (ghrelin) and 4FOA (Wnt).
Figure 4.
Figure 4.
Ghrelin processing pathway involves a unique serine octanoylation modification. Several proteolytic steps and serine octanoylation by GOAT precede ghrelin secretion into the bloodstream, where it undergoes esterase-catalysed deacylation while in circulation. The dotted arrow (left) reflects the potential for local reacylation of des-acyl ghrelin by cells with plasma membrane exposed GOAT. Figure created with Biorender.com.
Figure 5.
Figure 5.
The GOAT acyl-donor binding site selects for an eight-carbon acyl chain. (a) The acyl-donor binding site is exposed on the cytoplasmic face of GOAT; (b) Cutaway view of the acyl chain of octanoyl-CoA binding into a hydrophobic pocket within the enzyme internal channel. (c) Alanine mutagenesis of residues contacting octanoyl-CoA leads to either reduction (purple) or complete loss (red) of enzyme acylation activity. Figure reproduced from reference [115] under the terms of the Creative Commons CC-BY licence.
Figure 6.
Figure 6.
Computational model of human GOAT structure. The structure of hGOAT is shown in an ER-mimetic lipid membrane, with helices colour coded to the accompanying membrane topology diagram. Figure reproduced from reference [115] under the terms of the Creative Commons CC-BY licence.
Figure 7.
Figure 7.
Experimentally determined structures of MBOAT family members. The structure of DltB (PDB 6BUI) was determined by X-ray crystallography, with the other MBOAT structures solved by cryoelectron microscopy (DGAT1: PDB 6VPO [121], PDB 6VYI [122]; ACAT1/SOAT1: PDB 6L48 [123], PDB 6VUM [124] and PDB 6P2P [125]). Cryo-EM structures of DGAT1 solved by two laboratories report similar dimeric structures. ACAT1/SOAT1 was solved by three different laboratories, with two groups reporting tetrameric structures and the remaining group yielding a ACAT1/SOAT1 dimer. (a) DltB is shown in cyan. (b) DGAT, with each monomer in the dimer denoted by shades of green. Lipids are shown in magenta. (c) ACAT/SOAT, with each monomer depicted in shades of red. O-succinylbenzoyl-N-CoenzymeA, orange; cholesterol, yellow; nevanimibe, purple and blue; coenzyme A, violet; lipids, green. Figure created with PyMol.
Figure 8.
Figure 8.
Proposed reaction cycle for transmembrane ghrelin octanoylation by GOAT. The two substrates for GOAT, ghrelin (GSSFL-ghrelin) and octanoyl-CoA, enter the enzyme internal channel from the ER lumen and cytoplasm, respectively. Acyl transfer of the octanoyl chain to the ghrelin serine hydroxyl is catalysed by interaction with His-338, followed by octanoylated ghrelin dissociation to the ER lumen and coenzyme A release back to the cytoplasm. Figure created with BioRender.com.
Figure 9.
Figure 9.
Esterases in circulation with demonstrated ghrelin deacylation activity. Each of these esterases has been shown to hydrolyse the octanoyl serine within GOAT. Butyrlcholinesterase (PDB 4BDS); α2-macroglobulin (PDB 5A42); APT1 (PDB 5SYM); Notum (PDB 4WBH). Figure created with Pymol.
Figure 10.
Figure 10.
Representative classes of GOAT inhibitors. The current range of reported GOAT inhibitors can be divided into three main classes: product-mimetic peptide inhibitors, substrate and bisubstrate-mimetic peptide inhibitors, and small-molecule ‘drug-like’ inhibitors.
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