Prohormones

Polypeptide hormones are synthesized as part of a larger precursor molecule or prohormone. Cleavage of the prohormone by specific cellular enzymes, ie, peptidases, produces the secreted form of the hormone. In some cases, multiple bioactive hormones are produced from a single prohormone. 

In the anterior pituitary gland (see Hormones, anteriorpituitaryhormones), both adrenocorticotropic hormones (ACTH) and the endogenous opiate hormone, P-endorphin, are synthesized from a common prohormone (2) (see Opioids,endogenous). In the adrenal medulla, five to seven copies of another opiate hormone, methionine—enkephalin (Met-enkephalin), and one copy of leucine—enkephalin (Leu-enkephalin) are synthesized from each precursor molecule (3). 

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

The most significant metabolic product of testosterone is DHT, since in many tissues, including prostate, external genitalia, and some areas of the skin, this is the active form of the hormone. The plasma content of DHT in the adult male is about one-tenth that of testosterone, and approximately 400 ig of DHT is produced daily as compared with about 5 mg of testosterone. About 50-100 ig of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH-depen-dent 5oi-reductase (Figure 42-6). Testosterone can thus be considered a prohormone, since it is converted into a much more potent compound (dihydrotestosterone) and since most of this conversion occurs outside the testes. Some estradiol is formed from the peripheral aromatization of testosterone, particularly in males. 

A deiodinase removes 1 from the inactive mono-and diiodothyronine molecules in the thyroid. This mechanism provides a substantial amount of the 1 used in T3 and T4 biosynthesis. A peripheral deiodinase in target tissues such as pituitary, kidney, and fiver selectively removes T from tfie 5 position of T4 to make T3 (see Figure 42-2), wfiicfi is a mucfi more active molecule. In this sense, T4 can be thought of as a prohormone, though it does have some intrinsic activity. 

A several-week supply of T3 and T4 exists in the thy-roglobidin that is stored in colloid in the lumen of the thyroid foUicles. These hormones can be released upon stimulation by TSH. This is the most exaggerated example of a prohormone, as a molecule containing approximately 5000 amino acids must be first synthesized, then degraded, to supply a few molecules of the active hormones T4 and T3. 

Vitamin A (retinol), present in carnivorous diets, and the provitamin (P-carotene), found in plants, form retinaldehyde, utilized in vision, and retinoic acid, which acts in the control of gene expression. Vitamin D is a steroid prohormone yielding the active hormone derivative calcitriol, which regulates calcium and phosphate metaboUsm. Vitamin D deficiency leads to rickets and osteomalacia. 

The mu, kappa, and delta opioid receptors have been found to interact with endogenous peptide ligands that share certain pharmacologic properties with opioid drugs. These peptide ligands are derived from at least three different prohormones located in both... 

The third prohormone from which opioid peptides are derived is pro-opiomelanocortin, which yields a number of nonopioid and opioid peptide products (O Donohue and Dorsa 1982). Of these products, beta-endorphin, an untriakontapeptide isolated from camel pituitary gland by Li and Chung (1976)) is thought to interact primarily with mu and delta receptors. 

Despite the availability of a wide array of thyroid hormone products, it is clear that synthetic levothyroxine (LT4) is the treatment of choice for almost all patients with hypothyroidism. LT4 mimics the normal physiology of the thyroid gland, which secretes mostly T4 as a prohormone. As needed, based on metabolic demands, peripheral tissues convert thyroxine (T4)... 

Most of the physiologic activity of thyroid hormones is from the actions of T3. T4 can be thought of primarily as a prohormone. Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue deiodinases. These deiodinases allow end organs to produce the amount of T3 needed to control local metabolic functions. These enzymes also catabolize T3 and T4 to biologically inactive metabolites. Thyroid hormones bind to intracellular receptors and regulate the transcription of various genes. 

In the presence of renin, an enzyme produced by specialized cells in the kidney, angiotensinogen is split to form angiotensin I. This prohormone is then acted upon by angiotensin-converting enzyme (ACE) as the blood passes through the lungs to form Ag II. Angiotensin II acts directly on the adrenal cortex to promote aldosterone secretion. 

The term polyproteins is used for two different types of entity. The first refers to precursor polypeptides which are cleaved post-translationally into biologically active proteins or peptides of quite different functions. Examples of these include polyproteins of viruses and some prohormones of vertebrates (reviewed in Kennedy, 2000b). The other type is large proproteins which comprise tandem repetitions of identical or similar polypeptides that are post-translationally cleaved into multiple copies of biochemically similar functional entities. The nematode polyprotein allergens/antigens (NPAs) fall into this class (Fig. 16.1). 

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. 

Seidah, N. G. and Chretien, M. Proprotein and prohormone convertases a family of subtilases generating diverse bioactive polypeptides. Brain Res. 848 45-62,1999. 

Laurent, V., Jaubert-Miazza, L., Desjardins, R., Day, R. and Lindberg, I. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Endocrinology 145 519-528, 2004. 

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