Ho

Estradiol (an estrogen)

Estradiol (an estrogen)

Progesterone (a progestin)

Progesterone (a progestin)

2cholecalciferol

1,25 (OH)2 Cholecalciferol (a calciferol)

Examples of the six types of naturally occurring steroids.

cussed in Chapter 34, the discussion here is confined to the synthesis and secretion of polypeptide hormones.

Preprohormones and Prohormones. Like other proteins destined for secretion, polypeptide hormones are synthesized with a pre- or signal peptide at their amino terminal end that directs the growing peptide chain into the cisternae of the rough ER. Most, if not all, polypeptide hormones are synthesized as part of an even larger precursor or prepro-hormone. The prepeptide is cleaved off upon entry of the preprohormone into the rough ER, to form the prohormone. As the prohormone is processed through the Golgi apparatus and packaged into secretory vesicles, it is prote-olytically cleaved at one or more sites to yield active hormone. In many cases, preprohormones may contain the sequences for several different biologically active molecules. These active elements may, in some cases, be separated by inactive spacer segments of peptide.

Examples of prohormones that are the precursors for polypeptide hormones, which illustrate the multipotent nature of these precursors, are shown schematically in Figure 31.3. Note, for example, that proopiomelanocortin (POMC) actually contains the sequences for several biologically active signal molecules. Propressophysin serves as the precursor for the nonapeptide hormone arginine vaso-pressin (AVP). The precursor for TRH contains five repeats of the TRH tripeptide in one single precursor molecule.

In general, two basic amino acid residues, either lys-arg or arg-arg, demarcate the point(s) at which the prohormone will be cleaved into its biologically active components. Presumably, these two basic amino acids serve as specific recognition sites for the trypsin-like endopepti-dases thought to be responsible for cleavage of the prohormones. Although somewhat rare, there are documented cases of inherited diseases in which a point mutation involving an amino acid residue at the cleavage site results in an inability to convert the prohormone into active hormone, resulting in a state of hormone deficiency. Partially cleaved precursor molecules having limited biological activity may be found circulating in the blood in some of these cases.

In some disease states, large amounts of intact precursor molecules are found in the circulation. This situation may be the result of endocrine cell hyperactivity or even uncontrolled production of hormone precursor by nonen-docrine tumor cells. Although precursors usually have relatively low biological activity, if they are secreted in sufficiently high amounts, they may still produce biological effects. In some cases, these effects may be the first recognized sign of neoplasia.

Tissue-specific differences in the processing of prohormones are well known. Although the same prohormone gene may be expressed in different tissues, tissue-specific differences in the way the molecule is cleaved give rise to different final secretory products. For example, within alpha cells of the pancreas, proglucagon is cleaved at two positions to yield three peptides, illustrated in Figure 31.4 (left). Glucagon, an important hormone in the regulation of carbohydrate metabolism, is the best characterized of the three peptides. In contrast, in other cells of the gastrointestinal (GI) tract in which proglucagon is also produced, the molecule is cleaved at three different positions such that gli-centin, glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2) are produced (Fig. 31.4, right).

Intracellular Movement of Secretory Vesicles and Exocy-tosis. Upon insertion of the preprohormone into the cisternae of the ER, the prepeptide or signal peptide is rapidly cleaved from the amino terminal end of the molecule. The resulting prohormone is translocated to the Golgi appara-

Proglucagon

N-peptide

Glucagon

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Responses

  • lisa baumgaertner
    Are most polypeptide and protein hormones synthesized as prehormones?
    8 years ago

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