Ghrelin octanoylation mediated by an orphan lipid transferase.
The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function.
Gutierrez
Jesus A
JA
Integrative Biology, Eli Lilly and Company, 2001 West Main Street, Greenfield, IN 46140, USA. gutierrez_jesus_a@lilly.com
Solenberg
Patricia J
PJ
Perkins
Douglas R
DR
Willency
Jill A
JA
Knierman
Michael D
MD
Jin
Zhaoyan
Z
Witcher
Derrick R
DR
Luo
Shuang
S
Onyia
Jude E
JE
Hale
John E
JE
D000215:Acylation; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002210:Caprylates / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D017124:Conserved Sequence; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D054439:Ghrelin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010179:Pancreas / Q000201:enzymology; D010455:Peptides / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013270:Stomach / Q000201:enzymology
D002210:Caprylates; D054439:Ghrelin; D010455:Peptides; D012333:RNA, Messenger; D012694:Serine; D000217:Acyltransferases; C031492:octanoic acid