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

Jing Yang, Tong Jin Zhao, Joseph L. Goldstein, Michael S. Brown

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

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 residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [3H]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.

Original languageEnglish (US)
Pages (from-to)10750-10755
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number31
DOIs
StatePublished - Aug 5 2008

Fingerprint

Acyltransferases
Ghrelin
Serine
Acylation
Inhibition (Psychology)
Peptide Hormones
Baculoviridae
Drug Design
Appetite
Amides
Insects
Esters
Obesity
Cell Membrane
Amino Acids
Acids
Membranes

Keywords

  • Appetite control
  • In vitro
  • Inhibitors
  • Obesity
  • Octanoylation of proghrelin

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides. / Yang, Jing; Zhao, Tong Jin; Goldstein, Joseph L.; Brown, Michael S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 31, 05.08.2008, p. 10750-10755.

Research output: Contribution to journalArticle

@article{fefcba35745d4c85aa66ff3a98266b45,
title = "Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides",
abstract = "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 residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [3H]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.",
keywords = "Appetite control, In vitro, Inhibitors, Obesity, Octanoylation of proghrelin",
author = "Jing Yang and Zhao, {Tong Jin} and Goldstein, {Joseph L.} and Brown, {Michael S.}",
year = "2008",
month = "8",
day = "5",
doi = "10.1073/pnas.0805353105",
language = "English (US)",
volume = "105",
pages = "10750--10755",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "31",

}

TY - JOUR

T1 - Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides

AU - Yang, Jing

AU - Zhao, Tong Jin

AU - Goldstein, Joseph L.

AU - Brown, Michael S.

PY - 2008/8/5

Y1 - 2008/8/5

N2 - 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 residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [3H]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.

AB - 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 residue 3 of proghrelin, which is the known site of acylation. GOAT also transferred [3H]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.

KW - Appetite control

KW - In vitro

KW - Inhibitors

KW - Obesity

KW - Octanoylation of proghrelin

UR - http://www.scopus.com/inward/record.url?scp=49449085708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49449085708&partnerID=8YFLogxK

U2 - 10.1073/pnas.0805353105

DO - 10.1073/pnas.0805353105

M3 - Article

VL - 105

SP - 10750

EP - 10755

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 31

ER -