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BIOLOGICAL SCIENCES / CELL BIOLOGY
Ghrelin octanoylation mediated by an orphan lipid transferase
*Integrative Biology, Eli Lilly and Company, 2001 West Main Street, Greenfield, IN 46140; and Biotechnology Discovery Research and Cancer Inflammation and Cell Survival, Eli Lilly and Company, Indianapolis, IN 46285
Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 28, 2008 (received for review January 23, 2008)
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.
acylation | membrane-bound O-acyl transferase
Author contributions: J.A.G. and P.J.S. contributed equally to this work; J.A.G., P.J.S., D.R.P., J.E.O., and J.E.H. designed research; J.A.G., P.J.S., D.R.P., J.A.W., M.D.K., Z.J., and S.L. performed research; D.R.W. contributed new reagents/analytic tools; J.A.G., P.J.S., D.R.P., J.A.W., M.D.K., Z.J., and J.E.H. analyzed data; and J.A.G. and J.E.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The GOAT sequence reported in this paper has been deposited in the GenBank database [EU518498 (human), EU518496 (rat), EU518495 (mouse), and EU518497 (zebrafish)].
See Commentary on page 6213.
This article contains supporting information online at www.pnas.org/cgi/content/full/0800708105/DCSupplemental.
To whom correspondence should be addressed. E-mail: gutierrez_jesus_a{at}lilly.com
© 2008 by The National Academy of Sciences of the USA
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