Proteolytic hormone precursors

INSULIN. Some protein hormones are synthesized in the form of inactive precursor molecules, from which the active hormone is derived by proteolysis. For instance, insulin, an important metabolic regulator, is generated by proteolytic excision of a specific peptide from proinsulin (Figure 15.3). 

FIGURE 18-7 Processing of the proopiomelanocortin (POMC) precursor proceeds in an ordered, stepwise fashion. Cleavage of the POMC precursor occurs at seven sites, with some of the reactions being tissue-specific. The circled numbers indicate the temporal order of cleavage in tissues where these proteolytic events occur. ACTH, adrenocorticotropic hormone CLIP, corticotropin-like intermediate lobe peptide JP, joining peptide LPH, lipotropin MSH, melanocyte-stimulating hormone PC, prohormone convertase. 

Many proteins are synthesized in inactive forms, termed proproteins. Insulin is created as an inactive single polypeptide chain and must be cleaved to create the active hormone. Many proteolytic enzymes are made as inactive precursors and must be cleaved to form enzymatically active molecules. 

Hydrophilic hormones and other water-soluble signaling substances have a variety of biosynthetic pathways. Amino acid derivatives arise in special metabolic pathways (see p. 352) or through post-translational modification (see p. 374). Proteohormones, like all proteins, result from translation in the ribosome (see p. 250). Small peptide hormones and neuropeptides, most of which only consist of 3-30 amino acids, are released from precursor proteins by proteolytic degradation. 

Somatostatin (or somatotropin release-inhibiting factor [SRIF]) occurs primarily as a 14-amino acid peptide, although a 28-amino acid form also exists. As with the other hypothalamic peptides, it is formed by proteolytic cleavage of a larger precursor. Somatostatin, originally isolated from the hypothalamus, is also in many other locations, including the cerebral cortex, brainstem, spinal cord, gut, urinary system, and skin. Somatostatin inhibits the secretion of many substances in addition to growth hormone (Table 59.1). 

Many proteins are formed as inactive precursors and become activated by proteolysis. The inactive precursors are termed proenzymes, zymogens or - for hormones like e.g. insulin - prehormones. Processing to the active form occius in a cell- and tissue-specific way and usually requires a specific protease. Activation can also occur intramolecu-larly by autoproteolysis. In most cases, short sequences of the protease substrate serve as a recognition signal for the attack of the processing protease. Of the numerous examples of proteolytic processing of proteases only the digestive proteases will be discussed in more detail. 

Many other protein hormones are also synthesized as inactive precmsors. Examples are insulin, which is formed in a two-step proteolytic process from the precursor pre-pro-insulin. Another noteworthy example is that of pre-pro-opiomelanocortin, which is the precursor for eight peptide hormones and neuropeptides in the epiphyse. 

Another example of processing of glycoproteins is found in the synthesis of pituitary hormones. ACTH, /3LPH, a-MSH, and /3-endorphin are synthesized from a common precursor in the neurointermediate lobe. Controlled, proteolytic cleavage liberates the final products, which are then secreted. Numerous other examples could be mentioned.3SS 393... 

Section B,10). Precursor proteins have been identified for many other peptide hormones, even those with very short chains.29-303 Proteolytic cleavages and other processing reactions occur within the secretory pathways of organisms from yeast to humans.30b/C... 

This chapter deals with various aspects of metabolism of protein hormones, in particular, how these regulatory molecules are synthesized and stored as precursor molecules and proteolytically processed to generate biologically active hormones. The mechanisms involved in secretion and degradation are also described. 

Several of the small physiologically active peptides now are known to be derived from a single protein precursor synthesized by the pituitary gland (43). As shown in Figure 9, ACTH (adrenocorticotropic hormone), /3-LPH ( -lipotropic hormone), /3-MSH ( -melanocyte-stimulating hormone), /3-endorphin, and enkephalin result from the specific proteolytic cleavage of a precursor protein of approximately 8,000 daltons. 

Insulin [IN suh lin] is a small protein consisting of two polypeptide chains that are connected by disulfide bonds. It is synthesized as a precursor protein (pro-insulin) that undergoes proteolytic cleavage to form insulin and peptide C, both of which are secreted by the p-cells of the pancreas.4 [Note Normal individuals secrete less pro-insulin than insulin, whereas NIDDM patients secrete high levels of the prohormone. Since radioimmunoassays do not distinguish between the two insulin types, NIDDM patients may have lower levels of the active hormone than the assay indicates. Thus measurement of circulating C peptide provides a better index of insulin levels.]... 

Some protein hormones are synthesized as inactive precursors. For example, insulin is derived from proinsulin by proteolytic removal of a peptide. 

The epidermal growth factor (EGF) domain is one example of a module that is present in several proteins (Figure 3-8). EGF is a small, soluble peptide hormone that binds to cells in the embryo and in skin and connective tissue in adults, causing them to divide. It is generated by proteolytic cleavage between repeated EGF domains in the EGF precursor protein, which is anchored in the cell membrane by a membrane-spanning domain. EGF modules are also present in other proteins and are liberated by proteolysis these proteins include tissue plasminogen activator (TPA), a protease that is used to dissolve blood clots In heart attack victims ... 

Nearly all peptide hormones are synthesized as inactive precursors and then converted to active hormones by proteolytic processing. Studies of the synthesis of insulin provided the first evidence of this phenomenon (see Figure 5.21). Insulin contains two polypeptide chains, of 21 and 30 residues, with two interchain disulfide bridges and one intrachain bridge (Figure 5.15). 

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