Alternative titles; symbolsGHRELIN O-ACETYLTRANSFERASE; GOATHGNC Approved Gene Symbol: MBOAT4Cytogenetic location: 8p12 Genomic coordinates (GRCh38): 8:30,13...
Alternative titles; symbols
HGNC Approved Gene Symbol: MBOAT4
Cytogenetic location: 8p12 Genomic coordinates (GRCh38): 8:30,131,453-30,148,767 (from NCBI)
▼ Cloning and Expression
Yang et al. (2008) cloned mouse Mboat4, which they called Goat, and identified orthologs from several vertebrate species, including human, by database analysis. The mouse and human proteins both contain 435 amino acids and have 8 putative transmembrane segments and conserved catalytic asparagine and histidine residues (asp307 and his338). Semiquantitative PCR of mouse tissues detected highest Goat expression in stomach, with lower expression in small intestine, colon, and testis.
By database analysis, functional screening, and RT-PCR and 5-prime RACE of human medullary thyroid carcinoma cell line mRNA, Gutierrez et al. (2008) cloned MBOAT4, which they called GOAT. RT-PCR detected high GOAT expression in stomach and pancreas and low expression in most other tissues examined.
By genomic sequence analysis, Gutierrez et al. (2008) mapped the MBOAT4 gene to chromosome 8p12.
▼ Gene Function
Yang et al. (2008) found that mouse Goat octanoylated ghrelin (GHRL; 605353), a 28-amino acid appetite-stimulating peptide hormone, following cotransfection of Goat and preproghrelin in cultured endocrine cell lines. Mutation analysis showed that Goat octanoylated ghrelin on ser3, a modification required for its endocrine effects. Asp307 and his338 of Goat were required for octanoylation.
Using small interfering RNA, Gutierrez et al. (2008) showed that knockdown of GOAT in human medullary thyroid carcinoma cells diminished octanoyl ghrelin synthesis. Cotransfection studies in human embryonic kidney cells demonstrated that GOAT octanoylated ghrelin peptides 1-28 and 1-27 on ser3. Minor levels of acetylated and butyrylated ser3 were also detected. Using medium supplemented with fatty acids ranging from acetate (C2) to hexadecanoic acid (C16), Gutierrez et al. (2008) found that GOAT could modify ghrelin ser3 with fatty acids up to tetradecanoic acid. Replacement of his338 of GOAT with ala completely abolished the ability of GOAT to octanoylate ghrelin.
In studies in mice lacking Mboat4 and mice overexpressing Mboat4, Kirchner et al. (2009) demonstrated that Mboat4 is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates, and links ingested lipids to energy expenditure and body fat mass. Kirchner et al. (2009) concluded that ghrelin acylation and the secretion of acylated ghrelin probably represent 2 independent processes, and that the ghrelin-MBOAT4 system is a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence, as had been commonly accepted.
Barnett et al. (2010) designed a peptide-based GOAT inhibitor called GO-CoA-Tat. Intraperitoneal administration of this inhibitor improved glucose tolerance and reduced weight gain in wildtype mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition.