title: Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation.
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.
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: Kayleigh R
authors.initials: KR
authors.lastname: McGovern-Gooch
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: Nivedita S
authors.initials: NS
authors.lastname: Mahajani
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: Ariana
authors.initials: A
authors.lastname: Garagozzo
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Schramm
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Hannah
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sieburg
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: John D
authors.identifier: 0000-0001-9518-2393
authors.initials: JD
authors.lastname: Chisholm
authors.affiliation: Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States.
authors.forename: James L
authors.identifier: 0000-0003-0444-1017
authors.initials: JL
authors.lastname: Hougland
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054439:Ghrelin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054439:Ghrelin; D008565:Membrane Proteins; D054852:Small Molecule Libraries; D014315:Triterpenes; D000217:Acyltransferases; C542776:MBOAT4 protein, human; C526983:Mboat4 protein, mouse; D003545:Cysteine