Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides

@article{Yang2008InhibitionOG,
  title={Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides},
  author={J. Yang and Tong-Jin Zhao and J. Goldstein and Michael S Brown},
  journal={Proceedings of the National Academy of Sciences},
  year={2008},
  volume={105},
  pages={10750 - 10755}
}
The discovery of ghrelin O-acyltransferase (GOAT) opens the way to the design of drugs that block the attachment of an octanoyl group to the appetite-stimulating peptide hormone ghrelin, potentially preventing obesity. Here, we develop a biochemical assay that uses membranes from insect cells infected with baculovirus encoding mouse GOAT. The GOAT-containing membranes transferred the [3H]octanoyl group from [3H]octanoyl CoA to recombinant proghrelin in vitro. Transfer depended on the serine at… Expand
Mechanistic analysis of ghrelin-O-acyltransferase using substrate analogs.
TLDR
Ghrelin substrates with amino-alanine in place of Ser3 demonstrated that GOAT can catalyze the formation of an octanoyl-amide bond at a similar rate compared with the natural reaction, and the conserved His338 residue was required both for Ser3 and amino-Ala3 ghrelin substrateates, suggesting that His338 may have a key catalytic role beyond that of a general base. Expand
Ghrelin O-acyltransferase (GOAT) has a preference for n-hexanoyl-CoA over n-octanoyl-CoA as an acyl donor.
TLDR
In vitro activity of GOAT was analyzed using the recombinant enzyme and it was found that, although the main active form of ghrelin is modified by n-octanoic acid, GOAT had a strong preference for n-hexanoyl-CoA over n- octanoysl- CoA as an acyl donor. Expand
Structure-activity analysis of human ghrelin O-acyltransferase reveals chemical determinants of ghrelin selectivity and acyl group recognition.
TLDR
Bioinformatics analysis supports the conclusion that gh Relin is a unique substrate for hGOAT within the human proteome, providing further justification for the ghrelin-hGOAT system as a desirable drug target. Expand
Functional group and stereochemical requirements for substrate binding by ghrelin O-acyltransferase revealed by unnatural amino acid incorporation.
TLDR
This study shows that small peptide mimics of ghrelin substituted with 2,3-diaminopropanoic acid in place of the serine at the site of octanoylation act as submicromolar inhibitors of GOAT. Expand
Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation.
TLDR
A class of synthetic triterpenoids are identified that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT), providing the first evidence of the involvement of a nucleophilic cysteine residue in substrate acylations by a MBOAT family acyltransferase. Expand
Ghrelin octanoylation by ghrelin O-acyltransferase: Unique protein biochemistry underlying metabolic signaling.
TLDR
A review of recent advances in the understanding of the interactions and mechanisms leading to ghrelin modification by GOAT is examined, the potential sources for the octanoyl acyl donor required for gh Relin's activation are discussed, and the current landscape of molecules targeting GhrelinOctanoylation through GOAT inhibition is summarized. Expand
Ghrelin O-acyltransferase (GOAT), a specific enzyme that modifies ghrelin with a medium-chain fatty acid.
TLDR
GOAT, the only enzyme known to catalyze acyl modification of ghrelin, specifically modifies serine (or threonine) at the third position and does not modify other serine residues in Ghrelin peptides. Expand
Characterization of the Human Ghrelin O-acyltransferase Active Site
Ghrelin, first discovered in 1999, is a 28-amino acid peptide hormone involved in the regulation of appetite, insulin secretion and sensitivity, and many neurological effects such as learning,Expand
Ghrelin O-acyltransferase assays and inhibition.
TLDR
Recent progress in the development of cell and in vitro assays to measure GOAT action and the identification of several synthetic GOAT inhibitors are reviewed. Expand
Recent progress in the discovery of ghrelin O-acyltransferase (GOAT) inhibitors.
TLDR
Over the past decade, several small-molecule based approaches have appeared dealing with the discovery of compounds able to modulate this enzyme for the treatment of obesity and type 2 diabetes, but compounds modulating the activity of the GOAT enzyme do not yet represent clinical options. Expand
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