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

135 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • General

Cite this