Hormone prohormone

The concept that thymic hormones exist is now well accepted. However, many controversies still persist because of the multiplicity of different thymic products that have been isolated from thymus tissue over the past several decades. Many of the peptides appear to fulfill at least some of the accepted criteria for categorization as true thymic hormones. However, it is still unclear whether the various thymic polypeptides are components of a single thymic hormone (prohormone) that is capable of exhibiting the complete gamut of biologic properties ascribed to all of the different thymic peptides or whether each peptide alone or in certain combinations with other factors, at both intrathymic and extrathymic locations, regulates specific steps of T cell maturation. In this section we will review the biologic properties attributable to thymic factors in both animals and man. 

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). 

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 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. 

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. 

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. 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

As would be expected of active protein secreting cells, glandular epithelial tissue, the cytokine secreting cells of the immune system and the blood vessel endothelium, have an extensive internal structure consisting of rough endoplasmic reticulum and numerous mitochondria. Peptide hormones, growth factors and cytokines like all proteins are synthesized by DNA transcription and mRNA translation. The primary transcript of the mRNA may code for an inactive prohormone which requires careful proteolysis to produce the active hormone, as for example in the case of insulin. Adrenocorticotropic hormone (ACTH) is particularly interesting in this respect because... 

The primary supply of vitamin in humans is not obtained from the diet but rather is derived from the ultraviolet photoconversion of 7-dehydrocholesterol to vitamin Ds in skin. Thus, vitamin Dj synthesis varies with the seasons. D3 is a prohormone and requires further metabolic conversion to exert biological activity in its target organs (Fig. 66.2). The liver and the kidney are the major sites of metabolic activation of this endogenous sterol hormone. The initial transformation of D3 occurs in the liver and is catalyzed by the enzyme 25-OH-D3-hydroxylase... 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

Peptide Hormones Peptide hormones may have from 3 to 200 or more amino acid residues. They include the pancreatic hormones insulin, glucagon, and somatostatin, the parathyroid hormone, calcitonin, and all the hormones of the hypothalamus and pituitary (described below). These hormones are synthesized on ribosomes in the form of longer precursor proteins (prohormones),... 

In some cases, prohormone proteins yield a single peptide hormone, but often several active hormones are carved out of the same prohormone. Pro-opiomelano-cortin (POMC) is a spectacular example of multiple hormones encoded by a single gene. The POMC gene encodes a large polypeptide that is progressively carved up into at least nine biologically active peptides (Fig. 23-6). The terminal residues of peptide hormones are often modified, as in TRH (Fig. 23-2). 

Retinoid Hormones Retinoids are potent hormones that regulate the growth, survival, and differentiation of cells via nuclear retinoid receptors. The prohormone retinol is synthesized from vitamin A, primarily in liver (see Fig. 10-21), and many tissues convert retinol to the hormone retinoic acid (RA). 

Function of Prohormones What are the possible advantages in the synthesis of hormones as prohormones ... 

Many secreted proteins, as well as smaller peptide hormones, are acted upon in the endoplasmic reticulum by tryptases and other serine proteases. They often cut between pairs of basic residues such as KK, KR, or RR.214-216 A substilisin-like protease cleaves adjacent to methionine.217 Other classes of proteases (e.g., zinc-dependent carboxypeptidases) also participate in this processing. Serine carboxypeptidases are involved in processing human prohormones.218 Among the serine carboxypeptidases of known structure is one from wheat219 and carboxypeptidase Y, a vacuolar enzyme from yeast.220 Like the pancreatic metallocarboxypeptidases discussed in Section 4, these enzymes remove one amino acid at a time, a property that has made carboxypeptidases valuable reagents for determination of amino acid sequences. Carboxypeptidases may also be used for modification of proteins by removal of one or a few amino acids from the ends. 

Plants do not only possess the tools for the perception of peptide signals, they also have enzymes potentially involved in the processing of peptide prohormones. The existence of such enzymes provides additional indirect evidence for a general role of peptide hormones in plant signal transduction processes. 

Thyroxine (T4) and the more potent triiodothyronine (T3) are cleaved from a large precursor protein called thyroglob-ulin. Thyroglobulin exists as a dimer of two identical polypeptides (Mr 330,000). It is a storage protein for iodine and can be considered a prohormone of the circulating thyroid hormones. Thyroglobulin is secreted into the lumen of the thyroid gland, where specific residues are iodinated in... 

Another issue is the dietary supplements commonly referred to as prohormones, which are touted as muscle builders and available legally at health food stores. In 1998 during the homerun race between baseball stars Mark McGuire and Sammy Sosa these supplements were propelled into the media spotlight. Mark McGuire announced he was quitting his use of the most popular prohormone, androstenedione (or andro ) to help boost his performance. DHEA is another popular one. Now under scrutiny by the DEA, FDA, and Federal Trade Commission, these prohormones are intermediates in the synthesis of testosterone, and can be converted to testosterone and other hormones in the body. 

Anterior pituitary hormones include growth hormone (GH), thyrotropin (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and adrenocorticotropin (ACTH). Another peptide, B-lipotropin (B-LPH), is derived from the same prohormone, proopiomelanocortin, as ACTH. B-LPH is secreted from the pituitary (along with ACTH), and is a precursor of the opioid peptide B-endorphin (see Chapter 31 Opioid Analgesics Antagonists). 

Relaxin is another peptide that can be extracted from the ovary. The three-dimensional structure of relaxin is related to that of growth-promoting peptides and is similar to that of insulin. Although the amino acid sequence differs from that of insulin, this hormone, like insulin, consists of two chains linked by disulfide bonds, cleaved from a prohormone. It is found in the ovary, placenta, uterus, and blood. Relaxin synthesis has been demonstrated in luteinized granulosa cells of the corpus luteum. 

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