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Submitted on May 5, 2004
Accepted on July 8, 2004
Department of Biochemistry and Nutrition and L. Deloyers Laboratory for Experimental Surgery, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
* To whom correspondence should be addressed. E-mail: cdelport{at}ulb.ac.be.
The endogenous ligand for the growth hormone secretagogue receptor is ghrelin, a peptide recently purified from the stomach. Ghrelin is n-octanoylated on the Ser3 residue and this modification is essential for its interaction with the receptor. The degradation of ghrelin by rat and human serum, purified commercial enzymes and tissues homogenates was analyzed by combining HPLC and mass spectrometry. In serum, ghrelin was desoctanoylated, without proteolysis. The desoctanoylation was significantly reduced by phenylmethylsulfonyl fluoride (PMSF), a serine proteases and esterases inhibitor. In rat serum, the carboxylesterase inhibitor bis-p-nitrophenyl-phosphate (BNPP) totally inhibited ghrelin desoctanoylation and a correlation was found between ghrelin desoctanoylation and carboxylesterase activity. Moreover, purified carboxylesterase degraded ghrelin. Thus, carboxylesterase could be responsible for ghrelin desoctanoylation in that species. In human serum, ghrelin desoctanoylation was partially inhibited by eserine salicylate and sodium fluoride, two butyrylcholinesterase inhibitors, but not by BNPP and ethylenediamine tetraacetic acid (EDTA). Purified butyrylcholinesterase was able to degrade ghrelin, and there was a correlation between the butyrylcholinesterase and ghrelin desoctanoylation activities in human sera. This suggested that several esterases, including butyrylcholinesterase, contributed to ghrelin desoctanoylation in human serum. In contact with tissues homogenates, ghrelin was degraded by both desoctanoylation and N terminal proteolysis. We identified five cleavage sites in ghrelin between residues -Ser2-(acyl)Ser3- (stomach and liver), -(acyl?)Ser3-Phe4- (stomach, liver and kidney), -Phe4-Leu5- (stomach and kidney), -Leu5-Ser6- and -Pro7-Glu8- (kidney). In all cases, the resulting fragments were biologically inactive.
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