Biosynthesis and Degradation

Ghrelin is a motilin-related, growth hormone-releasing and orexigenic peptide that was originally isolated from the stomach by Kojima and colleagues (1999). The ghrelin peptide is a 28-amino-acid protein with a fatty-chain modification on the amino-terminal third amino acid, which seems to be important for some but not all of its biological functions (Fig. 4.26). Ghrelin (molecular weight: 3314) displays a high degree of homology in various mammals. Ghrelin is derived from a 117-amino-acid precursor peptide, named preproghrelin.

The strong GH-releasing activity of ghrelin is mediated by the activation of the growth hormone secretagogue (GHS) receptor type 1a (GHS-R1a). Interestingly, ghrelin mainly circulates as des-octanoyl ghrelin (i.e. without an esterifica-tion of Ser3), a form of the protein that is unable to stimulate GHS-R1a. This non-acylated ghrelin, which is present in human serum in far greater quantities than acylated ghrelin, seems to be devoid of any endocrine action, with the exception of some non-endocrine actions, including cardiovascular and antiproli-ferative effects that are probably due to an interaction with different GHS-R subtypes or receptor families (van der Lely et al. 2004).

Shortly after the identification of ghrelin, a further protein was isolated and named des-Gln14-ghrelin. This protein is a 27-amino-acid protein with a sequence similar to that of ghrelin. The only difference is that it lacks Gln in position 14. Similar to ghrelin, this molecule also requires the n-octanoylation of Ser3 for its biological activity. These two peptides, ghrelin and des-Gln14-ghre-lin, are derived from a single gene which produces two alternative, distinct mRNAs. des-Gln14-ghrelin, like ghrelin, is an endogenous ligand for GHS-R 1a and it seems to possess the same biological activities as ghrelin. However, des-

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