Activation hormone

Amino acid-derived hormones include the catecholamines, epinephrine and norepinephrine (qv), and the thyroid hormones, thyroxine and triiodothyronine (see Thyroid AND ANTITHYROID PREPARATIONS). Catecholamines are synthesized from the amino acid tyrosine by a series of enzymatic reactions that include hydroxylations, decarboxylations, and methylations. Thyroid hormones also are derived from tyrosine iodination of the tyrosine residues on a large protein backbone results in the production of active hormone. 

Thyroid Hormones. Iodine, absorbed as P, is oxidized in the thyroid and bound to a thyroglobulin. The resultant glycoprotein, mol wt 670,000, contains 120 tyrosine residues of which ca two-thirds are available for binding iodine in several ways. Proteolysis introduces the active hormones 3,5,3 -triiodothyronine (T ) and 3,5,3, 5 -tetraiodothyronine (T, (thyroxine) in the ratio Ty.T of 4 1 (121,122). 

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). 

The formation of triiodothyronine (T3) and tetra-iodothyronine (thyroxine T4) (see Figure 42—2) illustrates many of the principles of diversity discussed in this chapter. These hormones require a rare element (iodine) for bioactivity they are synthesized as part of a very large precursor molecule (thyroglobuhn) they are stored in an intracellular reservoir (colloid) and there is peripheral conversion of T4 to T3, which is a much more active hormone. 

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. 

Lead has been shown to decrease circulating levels of the active form of vitamin D (1,25-dihydroxy-vitamin D) in children. The conversion of vitamin D to this active hormonal form takes place via hydroxylation to 25-hydroxyvitamin D in the liver, followed by 1-hydroxylation in the mitochondria of the renal tubule by a complex cytochrome P-450 (heme-containing) system (Mahaffey et al. 1982 Rosen and Chesney 1983). Comparisons of the serum 1,25-dihydroxyvitamin D levels in children with blood lead levels of 33 g/dL with those in children with severe renal insufficiency (Rosen et al. 1980) and in children with an inborn error of vitamin D metabolism in which the 1-hydroxylase system or component... 

Derived from the amino acid tyrosine, thyroid hormones are unique because they contain iodine. At this time, its incorporation into thyroid hormones is the only known use for iodine in the body. There are two thyroid hormones, named for the number of iodides added to the tyrosine residues of the thyroglobulin triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine). Although significantly more T4 is synthesized by the thyroid gland, T3 is the active hormone. At the target tissue, T4 is deiodoninated to form the more potent T3. 

TSH-secreting pituitary tumors release biologically active hormone that is unresponsive to normal feedback control. The tumors may cosecrete... 

Mercuric chloride, given for short time, has been reported to inhibit Na + /K + -ATPase in hog thyroid membranous preparation [149]. The blood T4 (thyroxine) levels were reduced and iodotyrosine deiodinase was inhibited, and it was suggested that mercurials might cause a coupling defect in the synthesis of iodothyronines. In mouse thyroid serum T4 level was affected by mercuric chloride, while serum T3 was not [ 150 ]. It was suggested that thyroidal secretion of T4 was inhibited by mercuric chloride, but the peripheral conversion of T4 to T3 might not be affected in the maintenance of an active hormone level. 

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... 

Figure 4.22 Insulin is produced from pro insulin by proteolysis. Active hormone and inactive C-peptide are co-secreted...

Gougat, C., D. Jaffuel, R. Gagliardo, C. Henriquet, J. Bousquet, P. Demoly, and M. Mathieu. 2002. Overexpression of the human glucocorticoid receptor alpha and beta isoforms inhibits AP-1 and NF-kappaB activities hormone independently. J Mol Med 80(5) 309-18. 

Second messengers often involved Protein kinases activated Hormone-receptor complex binds hormone response elements (HRE, of enhancer regions) inDNA... 

During fasting, the decrease in insulin and the increase in epinephrine activate hormone-sensitive lipase in fat cells, allowing fatty acids to be released into the circulation. 

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. 

The hormone triiodothyronine (T3) accelerates both total energy expenditure and protein degradation. The hormone secreted by the thyroid gland is thyroxine, which is converted to the active hormone T3 in a process that removes an iodine atom from the 5 position of the thyronine ring. If, however, an iodine atom is removed from the 3 position, the result is the formation of reverse-Ts... 

Smooth muscle differs from skeletal muscle in various ways. Smooth muscles—which are found, for example, in blood vessel walls and in the walls of the intestines—do not contain any muscle fibers. In smooth-muscle cells, which are usually spindle-shaped, the contractile proteins are arranged in a less regular pattern than in striated muscle. Contraction in this type of muscle is usually not stimulated by nerve impulses, but occurs in a largely spontaneous way. Ca (in the form of Ca -calmodulin see p.386) also activates contraction in smooth muscle in this case, however, it does not affect troponin, but activates a protein kinase that phosphorylates the light chains in myosin and thereby increases myosin s ATPase activity. Hormones such as epinephrine and angiotensin II (see p. 330) are able to influence vascular tonicity in this way, for example. 

PTU possesses special benefit it inhibits peripheral deiodination, thereby blocking the conversion of thyroxine to the active hormone tri-iodothyronine. PTU is rapidly absorbed from the gut, reaching peak blood levels within one hour, and is excreted in urine as the inactive glucuronide within 24 hours. In contrast methimazole which is absorbed at variable rates, is excreted slower (only 65-70% within 48 hours in urine). The short plasma half-life of... 

The HREs are components of the control region of hormone-regulated promotors. Typically, the binding of the activated, hormone-bound receptor to the HRE stimulates the expression of the cognate genes. The mechanisms of transcription activation still remains speculative. Many proteins have been identified which act as coactivators, i.e. they interact with the activated receptor (review Glass et al., 1997). The nature of these proteins suggest that at least two, separate but not mutually exclusive pathways of transcription activation must be considered ... 

Fig. 4.11. Principle of signal transduction by RXR heterodimers. The activated hormone can be made available to the RXR heterodimer in three different ways, a) The hormone (e.g. T3 hormone) is synthesized in endocrinal tissue and reaches the DNA-bound RXR-T3R heterodimer in the nucleus via passive transport, b) The active hormone is formed in the cytosol from an inactive apo-hormone (as for, e.g. 9-ds-retinoic add), c) The hormone is synthesized intracellularly. In aU three cases, the binding of the hormone-RXR-heterodimeric complex is the signal that induces transcription activation of the downstream genes. After Mangelsdorf and Evans, 1995.

The insulin monomer is of 6000 molecular weight, and either the monomer or the dimer is the active hormone. Thus in fact the zinc that binds the molecule into hexamers is not of physiological interest. What is... 

All of these hormones produce their effects after a characteristic lag period of 30 minutes to several hours—the time required for the synthesis of new proteins. This means that the gene-active hormones cannot be expected to alter a... 

The effects of these agents can persist for hours or days after the agonist concentration has been reduced to zero. The persistence of effect is primarily due to the relatively slow turnover of most enzymes and proteins, which can remain active in cells for hours or days after they have been synthesized. Consequently, it means that the beneficial (or toxic) effects of a gene-active hormone usually decrease slowly when administration of the hormone is stopped. 

In the placenta, there are 17P-HSDs that reduce androstenedione to testosterone (in rodents) and estrone to estradiol (in rodents and humans) and 17P-HSDs that promote the opposite activity, possibly protecting the fetus from highly active hormones (Peltoketo et al.,... 

T FIGURE 10-20 Vitamin D3 production and metabolism, (a) Cholecalciferol (vitamin D3) is produced in the skin by UV irradiation of 7-dehydrocholesterol, which breaks the bond shaded pink. In the liver, a hydroxyl group is added at C-25 (pink) in the kidney, a second hydroxylation at C-1 (pink) produces the active hormone, 1,25-dihydroxycholecalciferol. This hormone regulates the metabolism of Ca2+ in kidney, intestine, and bone, (b) Dietary vitamin D prevents rickets, a disease once common in cold climates where heavy clothing blocks the UV component of sunlight necessary for the production of vitamin D3 in skin. On the left is a 21/2-year-old boy with severe rickets on the right, the same boy at age 5, after 14 months of vitamin D therapy. 

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). 

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