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Notum deacylates octanoylated ghrelin.

Yuguang Zhao1, Laura-Nadine Schuhmacher2, Morgan Roberts2

  • 1Division of Structural Biology, Wellcome Centre for Human Genetics, Oxford University, Oxford, OX3 7BN, UK.

Molecular Metabolism
|March 1, 2021
PubMed
Summary
This summary is machine-generated.

Notum, an enzyme, removes octanoyl lipids from ghrelin, acting as a ghrelin deacylase. This enzymatic activity is relevant under high-fat diet conditions, impacting acylated ghrelin levels.

Keywords:
Crystal structureDeacylationGhrelinMetabolismNotum

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • O-linked lipidation modifies Wnt and ghrelin proteins, impacting ligand activity.
  • Notum enzyme's Wnt-deacylase activity inhibits Wnt signaling.
  • The role of Notum in ghrelin deacylation was previously undetermined.

Purpose of the Study:

  • To determine if Notum can deacylate ghrelin.
  • To elucidate the mechanism of Notum-ghrelin interaction.
  • To investigate the physiological relevance of Notum in ghrelin deacylation.

Main Methods:

  • Mass spectrometry to detect ghrelin deacylation by Notum.
  • Co-crystallography to determine the structure of the Notum-ghrelin complex.
  • CRISPR/Cas technology for Notum tagging and localization studies.
  • Liver-specific Notum knockout mice to assess physiological roles.

Main Results:

  • Mass spectrometry confirmed Notum's ability to remove octanoyl groups from ghrelin.
  • Crystal structure revealed ghrelin's octanoyl group fitting into Notum's hydrophobic pocket.
  • Notum is produced in the liver and found in circulation.
  • Liver-specific Notum knockout mice showed increased circulating acylated ghrelin on a high-fat diet.

Conclusions:

  • Notum functions as a ghrelin deacylase, with potential physiological relevance under high-fat diets.
  • This study adds Notum to the list of enzymes modulating ghrelin's acylation state.
  • Multiple enzymes contribute to tuning ghrelin activity across physiological conditions.