Peptide Hormone Synthesis

Synthesis of steroid hormones (shown here) and of catecholamines (see Figure 21.32) and thyroid hormones (Figure 21.19), occur via straightforward metabolic pathways.

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).

The first product of translation of the insulin gene is a 105-residue polypeptide called preproinsulin. Cleavage from preproinsulin of a 24-residue N-terminal "signal sequence" yields proinsulin, an 81-residue polypeptide. Proinsulin then undergoes folding, disulfide bond formation, and cleavage to give the two polypeptide chains of the active hormone, insulin. The signal sequence that is eventually cleaved from preproinsulin to form proinsulin is needed transport the protein through membranes (see here).

All known polypeptide hormones are synthesized in "prepro" form, with a signal sequence and additional sequence(s) that are cleaved out during maturation of the hormone.

A particularly interesting case is that seen when a single polypeptide sequence contains two or more distinct hormones. The most complex example is a pituitary multihormone precursor that contains sequences for - and -lipotropin, -, -, and -melanocyte-stimulating hormone (MSH), endorphin, enkephalin, and ACTH (Figure 23.10). This precursor, called pro-opiomelanocortin, derives its name from its role as precursor to endogenous opiates, melanocyte-stimulating hormone, and corticotropin. A remarkable fact about pro-opiomelanocortin is that it is cleaved at different sites in different cells, so that different cell types produce different ensembles of hormones derived from this one precursor.

Cleavage sites are shown in red in Figure 23.10. In the anterior pituitary, cleavage generates ACTH and -lipotropin, and further processing in the central nervous system yields endorphin and enkephalin, among other products.

1. Enkephalins

2. The Biology of Pleasure (endorphins and enkephalins)