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

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 infec... Full description

Journal Title: Proceedings of the National Academy of Sciences 05 August 2008, Vol.105(31), p.10750
Main Author: Jing Yang
Other Authors: Tong-Jin Zhao , Joseph L. Goldstein , Michael S. Brown
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0805353105
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recordid: pnas_s105_31_10750
title: Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides
format: Article
creator:
  • Jing Yang
  • Tong-Jin Zhao
  • Joseph L. Goldstein
  • Michael S. Brown
subjects:
  • Sciences (General)
ispartof: Proceedings of the National Academy of Sciences, 05 August 2008, Vol.105(31), p.10750
description: 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 [ 3 H]octanoyl group from [ 3 H]octanoyl CoA to recombinant proghrelin in vitro . Transfer depended on the serine at residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [ 3 H]octanoyl to a pentapeptide containing only the N-terminal five amino acids of proghrelin. GOAT activity could be inhibited by an octanoylated ghrelin pentapeptide, and its potency was enhanced 45-fold when the octanoylated serine-3 was replaced by octanoylated diaminopropionic acid. The data suggest that GOAT is subjected to end-product inhibition and this inhibition is better achieved with substrates having the octanoyl group attached through an amide linkage rather than the corresponding ester. These insights may facilitate the future design of useful inhibitors of GOAT. appetite control in vitro inhibitors obesity octanoylation of proghrelin
language: eng
source:
identifier: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.0805353105
fulltext: fulltext_linktorsrc
issn:
  • 0027-8424
  • 00278424
  • 1091-6490
  • 10916490
url: Link


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titleInhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides
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descriptionThe 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 [ 3 H]octanoyl group from [ 3 H]octanoyl CoA to recombinant proghrelin in vitro . Transfer depended on the serine at residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [ 3 H]octanoyl to a pentapeptide containing only the N-terminal five amino acids of proghrelin. GOAT activity could be inhibited by an octanoylated ghrelin pentapeptide, and its potency was enhanced 45-fold when the octanoylated serine-3 was replaced by octanoylated diaminopropionic acid. The data suggest that GOAT is subjected to end-product inhibition and this inhibition is better achieved with substrates having the octanoyl group attached through an amide linkage rather than the corresponding ester. These insights may facilitate the future design of useful inhibitors of GOAT. appetite control in vitro inhibitors obesity octanoylation of proghrelin
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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 [ 3 H]octanoyl group from [ 3 H]octanoyl CoA to recombinant proghrelin in vitro . Transfer depended on the serine at residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [ 3 H]octanoyl to a pentapeptide containing only the N-terminal five amino acids of proghrelin. GOAT activity could be inhibited by an octanoylated ghrelin pentapeptide, and its potency was enhanced 45-fold when the octanoylated serine-3 was replaced by octanoylated diaminopropionic acid. The data suggest that GOAT is subjected to end-product inhibition and this inhibition is better achieved with substrates having the octanoyl group attached through an amide linkage rather than the corresponding ester. These insights may facilitate the future design of useful inhibitors of GOAT. appetite control in vitro inhibitors obesity octanoylation of proghrelin

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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 [ 3 H]octanoyl group from [ 3 H]octanoyl CoA to recombinant proghrelin in vitro . Transfer depended on the serine at residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [ 3 H]octanoyl to a pentapeptide containing only the N-terminal five amino acids of proghrelin. GOAT activity could be inhibited by an octanoylated ghrelin pentapeptide, and its potency was enhanced 45-fold when the octanoylated serine-3 was replaced by octanoylated diaminopropionic acid. The data suggest that GOAT is subjected to end-product inhibition and this inhibition is better achieved with substrates having the octanoyl group attached through an amide linkage rather than the corresponding ester. These insights may facilitate the future design of useful inhibitors of GOAT. appetite control in vitro inhibitors obesity octanoylation of proghrelin

pubNational Acad Sciences
doi10.1073/pnas.0805353105
urlhttp://www.pnas.org/content/105/31/10750.abstract
lad01Proceedings of the National Academy of Sciences
pages10750-10755
date2008-08-05