Tyrosine-derivative hormones

Intracellular metabolic activity may be modulated in response to extracellular conditions by hormones. Hormones are substances which act as chemical messengers between cells in different locations to alter the activity of the recipient cell. Three classes of hormones have been identified protein (polypeptide) hormones, steroid hormones and tyrosine-derivative hormones of which there are two distinct groups, the catecholamines and the thyroid hormones. The catecholamine hormones (adrenaline and noradrenaline) are produced by and secreted from the adrenal medulla. The thyroid hormones (thyroxine and triiodothyronine) are elaborated by and secreted from the thyroid gland. 

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. 

Figure 42-2. Chemical diversity of hormones. A. Cholesterol derivatives. B. Tyrosine derivatives. C. Peptides of various sizes D. Glycoproteins (TSH, FSH, LH) with common a subunits and unique P subunits.

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. 

Thioamides are reducing agents. They inhibit thyroid hormone synthesis by inhibiting the peroxidase enzymatic system, which catalyzes oxidation of iodide ions and iodine that are consumed in food, which is necessary for iodination of tyrosine derivatives. Thus they reduce the concentration of free iodine necessary to react with tyrosine derivatives, and they can also block oxidative addition reactions of mono- and diiodtyrosines, which form L-thyroxine and L-triiodothyronin. 

Figure 11-11 depicts the several structures relevant to this discussion. The thyroid hormones and precursors are all iodinated tyrosine derivatives, and their iodine content is undoubtedly a unique occurrence in mammals. 

Animal hormones essentially fall into four different chemical classes (1) amine-derived hormones, (2) peptide/protein hormones, (3) steroid hormones, and (4) lipid or phospholipid hormones. Amine-derived hormones such as catecholamines and thyroxine are derivatives of the amino acids tyrosine and tryptophan. Peptide hormones including insulin, growth hormone, and vasopressin consist of polypeptides ranging in length from 5 to 200 residues. Steroid hormones such as estrogen... 

Tyrosine or phenylalanine residues in position 2 are essential for activity. Replacement of the aromatic amino acid by serine inactivates the hormone completely. The phenylalanine derivative is less active than the tyrosine derivative, indicating that the hydroxyl group of tyrosine, although not essential, enhances the hormonal activity. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

III. Tyr protein kinases A. Cytosolic tyrosine kinases src, fgr, abl, etc.) B. Receptor tyrosine kinases (RTKs) Plasma membrane receptors for hormones such as epidermal growth factor (EGF) or platelet-derived growth factor (PDGE) Raf (a protein kinase)... 

In 1979, Ross et al 22i" measured the ODMR of tyrosine in glucagon and the derivative [12-homoarginine]glucagon to examine the effect of chemical modification of a lysine residue adjacent to Tyr-10 and Tyr-13. The guanidinated analogue had lower potency than glucagon in a fat cell hormone receptor assay. Since the tyrosine ODMR and other spectral properties of the polypeptide, including circular dichroism, were essentially identical, it was... 

Iodine is required for the formation of amino acids that act as thyroid hormones. The amino acids thyroxine and triiodothyronine, both derived from tyrosine, a protein amino acid, provide examples. 

Tyrosine is structurally related to and derived from phenylalanine. It is the metabolic precursor to dopamine, an important neurotransmitter. Tyrosine is also the precursor to the hormones epinephrine and norepinephrine and to melanin, the pigment of skin. 

Note that these structures are related to that for the amino acid tyrosine, from which they are derived. The adrenal glands, small pieces of tissue that ride on top of the kidneys, secrete these hormones. When they activate adrenergic receptors on the surface of muscle cells, adenylate cyclase is activated, increased cAMP results, and the cascade of events in muscle cells is started (figure 17.1). 

The thyroid hormone thyroxine (tetraiodo-thyronine, T4) and its active form triiodothyronine (T3) are derived from the amino acid tyrosine. The iodine atoms at positions 3 and 5 of the two phenol rings are characteristic of them. Post-translational synthesis of thyroxine takes place in the thyroid gland from tyrosine residues of the protein thyro-globulin, from which it is proteolytically cleaved before being released, iodothyronines are the only organic molecules in the animal organism that contain iodine. They increase the basal metabolic rate, partly by regulating mitochondrial ATP synthesis, in addition, they promote embryonic development. 

Phenylalanine, tyrosine, and tryptophan are converted to a variety of important compounds in plants. The rigid polymer lignin, derived from phenylalanine and tyrosine, is second only to cellulose in abundance in plant tissues. The structure of the lignin polymer is complex and not well understood. Tryptophan is also the precursor of the plant growth hormone indole-3-acetate, or auxin (Fig. 22-28a), which has been implicated in the regulation of a wide range of biological processes in plants. 

Aromatic compounds arise in several ways. The major mute utilized by autotrophic organisms for synthesis of the aromatic amino acids, quinones, and tocopherols is the shikimate pathway. As outlined here, it starts with the glycolysis intermediate phosphoenolpyruvate (PEP) and erythrose 4-phosphate, a metabolite from the pentose phosphate pathway. Phenylalanine, tyrosine, and tryptophan are not only used for protein synthesis but are converted into a broad range of hormones, chromophores, alkaloids, and structural materials. In plants phenylalanine is deaminated to cinnamate which yields hundreds of secondary products. In another pathway ribose 5-phosphate is converted to pyrimidine and purine nucleotides and also to flavins, folates, molybdopterin, and many other pterin derivatives. 

Thyroid hormones are necessary for the development and function of cells throughout the body. The thyroid hormones thyroxine and tri-iodothyronine (Figure 7.7) are not peptides, but are actually simple derivatives of tyrosine. However, they are believed to be derived by degradation of a larger protein molecule. One... 

Melanin granules are secreted by melanocytes in the hair papilla and distributed to keratin in the hair cortex and inner layers of the hair sheath during normal development. Melanogenesis is subject to hormonal control and has been the focus of intensive genetic studies. Two main forms of melanin exist in human skin—eumelanin and phaeomelanin, both of which are derived from tyrosine through the action of tyrosinase (a cupro-enzyme) and possibly other key enzymes (with nickel, chromium, iron, and manganese as cofactors). Tyrosine is converted to dihydroxyphenylalanine and, via a series of intermediate steps, to indole-5,6-quinone, which polymerizes to eumelanin. Phaeomelanins are produced by a similar mechanism but with the incorporation of sulfur (as cysteine) by a nonenzymatic step in the oxidation process. 

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