Acth

y-lipotropin ß-endorphin

NH2-terminal peptide JP a-MSH CLIP y-lipotropin ß-endorphin melanotrope

FIGURE 3 Proteolytic processing of pro-opiomelanocortin (POMC). POMC after removal of the signal peptide is shown on the first line. The first cleavage by prohormone convertase 1 releases j-lipotropin. The second cleavage releases ACTH. A third cleavage releases the joining peptide (JP) to produce the principal secretory products of the corticotropes of the anterior pituitary gland. A third and fourth cleavage takes place in the melanotropes of the intermediate lobe and splits ACTH into a-melanocyte stimulating hormone (a-MSH) and the corticotropin-like intermediate lobe peptide (CLIP) and divides j-lipotropin into y-lipotropin and ^-endorphin. Some cleavage of j-lipotropin also takes place in the corticotrope. Additional post-translational processing (not shown) includes removal of the carboxyl-terminal amino acid from each of the peptides and glycosylation and phosphorylation of some of the peptide fragments. In neural tissue the NH2-terminal peptide shown by the clear area is also released to produce y3-MSH.

The ACTH-related peptides constitute a family because (1) they contain regions of homologous amino acid sequences that may have arisen through exon duplication and (2) because they all arise from the transcription and translation of the same gene (Fig. 3). The gene product is called pro-opiomelanocortin (POMC), which consists of 239 amino acids after removal of the signal peptide. The molecule contains 10 doublets of basic amino acids (arginine and lysine in various combinations), which are potential sites for cleavage by trypsin-like endopeptidases, called prohormone convertases. POMC is expressed by cells in the anterior lobe of the pituitary, the intermediate lobe, and various cells in the central nervous system; but tissue-specific differences in the way the molecule is processed after translation give rise to differences in the final secretory products. More than seven different enzymes carry out these post-translational modifications. The predominant products of human cortico-tropes are ACTH and ^-LPH. Because final processing of POMC occurs in the secretory granule, ^-LPH is secreted along with ACTH. Cleavage of ^-LPH also occurs to some extent in human corticotropes, so that some ^-endorphin may also be released, particularly when ACTH secretion is brisk. The intermediate lobe in some animals gives rise principally to a- and ^-MSH. Because the intermediate lobe of the pituitary gland of humans is thought to be nonfunctional except perhaps in fetal life, it is not discussed further. Some of the POMC peptides produced in hypothalamic neurons may play an important role in regulating food intake (see Chapter 42) and in coordinating overall responses to stress.

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