The biosynthesis of hormones occurs in specialized cells, usually present in endocrine glands, which express the enzymes that catalyze the steps of their formation and have any other necessary molecules required. Chapter 2 describes the production of the steroid hormones, while Chapters 5, 8, and 11 describe the biosynthesis of the thyroid hormones, eicosanoids, and epinephrine, respectively.

Protein and peptide hormones are biosynthesized in specific cells, through the well-known processes of transcription of a specific message encoded in the DNA of the gene for the protein and the translation of the RNA message (mRNA) into a protein. As with other proteins, variations in modifications to the initially produced mRNA and/or protein leads to deviation from the original “one gene, one protein” concept. The biosynthesis of peptide and protein hormones yields many examples of such deviations.

It is now quite well recognized that not only does one gene not lead to a single protein, one gene does not lead to a single RNA; that is, two or more RNA transcripts can arise through alternative processing of a single primary transcript. Figure 1 shows schematically how this happens. Exons are joined by splicing them together at very specific sites. Splice site recognition can vary from one cell to another, causing the primary transcript to differ between two cell types. The production of either calcitonin (CT) or calcitonin-gene-related pep tide (CGRP) was one of the first examples of alternative splicing to be elucidated. Alternative splicing is by no means an unusual method of generating multiple products of the same gene. While the exact percentage of protein coding genes subject to alternative splicing is not yet known, recent genomic analyses suggest that this number may be as high as 90%.

Fig1. Alternative splicing of mRNA for hormones. In eukaryotes almost all genes for proteins consist of regions of DNA that carry the code for the protein (exons; colored boxes) interrupted by noncoding sequences (gray line) in the primary mRNA transcript. Maturation of the primary transcript involves the splicing of these coding regions together as well as the addition of the 5′ cap and the poly A tail typical of eukaryotic mRNA. The splicing of the exons takes place in the nucleus and is carried out by large RNA/protein complexes called spliceosomes. It is the spliceosomes that are responsible for splice site (specific DNA sequences) selection. In the example shown, the spliceosomes of one cell type use the splice sites between exons 1, 2, and 4 while those in cell type 2 use exons 1, 3, and 4. The two mature RNAs thus encode different proteins. See Figure 9-10 for the example of calcitonin and calcitonin-gene-related peptide.

Another layer of variability in the final product of a gene is the post-translational processing of the initial protein product. Broadly speaking, this term includes the myriad modifications of the side chains of the amino acids as well as the addition of sugar or lipid moieties to the protein backbone. For this discussion, however, we will confine our attention to alteration of the initially translated protein by proteolytic cleavage, yielding smaller protein or peptide products. These cleavages are catalyzed by one of a family of proprotein convertases (PC1–PC7), serine endoproteases at cleavage sites in the precursor protein that are designated by two basic amino acids (Lys-Lys, Arg-Arg, or Lys-Arg). The reactions take place largely in the rough endoplasmic reticulum and in the Golgi apparatus as the hormone is being prepared for movement into secretory vesicles.

Figure 2 illustrates some examples of the post-translational cleavage events that yield active hormones. Most simply, virtually all hormones (and other secreted proteins) are synthesized as pre- or pre-pro-hormones, that is with one or two sequences to be removed, usually prior to secretion. The first of these is generally a signal for the initial intracellular localization of the new protein molecule. The mature form of parathyroid hormone (PTH) contains 84 amino acids from which pre- and pro-sequences of 25 and 6 amino acids, respectively, have been removed.

Fig2. Processing of pre- and pro-hormones. Many protein and peptide hormones (right) are synthesized within a larger precursor protein (left), of which three examples are shown here. The process is catalyzed by specific proteases that cleave the protein at specific sites (vertical lines), usually preceded by two basic (Lys, Arg) amino acids. Much of this processing takes place in the endoplasmic reticulum and Golgi apparatus and in secretory vesicles prior to the secretion of the hormones. As illustrated in the top example, many hormones are synthesized with one or two N-terminal portions which are sequentially removed to form the active hormone; see parathyroid hormone. In the second example, several different active peptides are within a single precursor protein, which is processed differently in different cell types; see proopiomelanocortin (POMC). Thirdly, a precursor protein can contain several copies of the hormone, each of which is excised at a pair of specific proteolytic sites, as in the case of the tri-peptide, TRH.

The second example in Figure 1 shows a precursor protein that contains within its sequence several biologically active peptides, and which can be differentially processed in different cell types. Such a situation is exemplified by proopiomelanocortin (POMC). ACTH (adrenocorticotrophic hormone) and other hormones are the processing products in pituitary corticotrophs whereas a different of set of peptides, including β-endorphins, result from the processing of the same precursor in the cells of the intermediate lobe of the brain.

Finally, the precursor protein can contain several copies of a single peptide hormone, as is the case for TRH (thyrotropin releasing hormone). This example, as well as that of insulin played important roles in the establishment of the idea that precursor protein molecules harbor active peptides within their sequences. In the case of insulin, this theory, based on the increasing availability of information from protein sequencing followed by that of DNA sequencing, solved the long standing question of the origin of the two subunits of insulin. As shown in Figure 6-5 it is now understood that insulin is synthesized as a single molecule. Disulfide bonds are formed to join two portions of the molecule and proteolytic cleavages release the two joined subunits from the pro-protein.

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Insulin resistance in skeletal muscle

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Diabetes heterogeneity

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Blood Glucose Regulation