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Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation
- Source :
- Biochemistry. 56:919-931
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small molecule therapeutics for treatment of obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence of the involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine-modifying electrophiles, revealing an important distinction in the activity and behavior between these closely related GOAT isoforms. This study establishes these compounds as potent small molecule inhibitors of ghrelin acylation and provides a foundation for the development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.
- Subjects :
- 0301 basic medicine
Acylation
Drug Evaluation, Preclinical
030209 endocrinology & metabolism
MBOAT
Biology
Biochemistry
Article
Small Molecule Libraries
Mice
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Animals
Humans
Structure–activity relationship
Cysteine
Enzyme Inhibitors
Cysteine metabolism
digestive, oral, and skin physiology
Membrane Proteins
Ghrelin
Triterpenes
Ghrelin O-acyltransferase
030104 developmental biology
chemistry
Acyltransferase
Acyltransferases
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 15204995 and 00062960
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....3aa89a2a1da829a898a401ce35805d80