Hormones: Diverse Structures for Diverse Functions:- Hormones Are Chemically Diverse
Mammals have several classes of hormones, distinguishable by their chemical structures and their modes of action (Table 23–1). Peptide, amine, and eicosanoid hormones act from outside the target cell via surface receptors. Steroid, vitamin D, retinoid, and thyroid hormones enter the cell and act through nuclear receptors. Nitric oxide also enters the cell, but activates a cytosolic enzyme, guanylyl cyclase . Hormones can also be classified by the way they get from the point of their release to their target tissue. Endocrine (from the Greek endon, “within,” and krinein, “to release”) hormones are released into the blood and carried to target cells throughout the body (insulin is an example). Paracrine hormones are released into the extracellular space and diffuse to neighboring target cells (the eicosanoid hormones are of this type). Au tocrine hormones are released by and affect the same cell, binding to receptors on the cell surface. Mammals are hardly unique in possessing hormonal signaling systems. Insects and nematode worms have highly developed systems for hormonal regulation, with fundamental mechanisms similar to those in mammals. Plants, too, use hormonal signals to coordinate the ac tivities of their various tissues . The study of hormone action is not as advanced in plants as in animals, but we do know that some mechanisms are shared. To illustrate the structural diversity and range of action of mammalian hormones, we consider representative examples of each major class listed in Table 23–1. 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),
FIGURE 1 Insulin. Mature insulin is formed from its larger precursor preproinsulin by proteolytic processing. Removal of a 23 amino acid segment (the signal sequence) at the amino terminus of preproinsulin and formation of three disulfide bonds produces proinsulin. Further proteolytic cuts remove the C peptide from proinsulin to produce mature insulin, composed of A and B chains. The amino acid sequence of bovine insulin is shown.
then packaged into secretory vesicles and proteolytically cleaved to form the active peptides. Insulinis a small protein (Mr5,800) with two polypeptide chains, A and B, joined by two disulfide bonds. It is synthesized in the pancreas as an inactive single-chain precursor, preproinsulin (Fig. 1), with an amino-terminal “signal sequence” that directs its passage into secretory vesicles. Proteolytic removal of the signal sequence and formation of three disulfide bonds produces proinsulin, which is stored in secretory granules in pancreatic cells. When elevated blood glucose triggers in sulin secretion, proinsulin is converted to active insulin by specific proteases, which cleave two peptide bonds to form the mature insulin molecule. In some cases, prohormone proteins yield a single peptide hormone, but often several active hormones arecarved out of the same prohormone. Pro-opiomelanocortin (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.2). The terminal residues of peptide hormones are often modified, as in TRH .
FIGURE 2 Proteolytic processing of the pro opiomelanocortin (POMC) precursor. The initial gene product of the POMC gene is a long polypeptide that undergoes cleavage by a series of specific proteases to produce ACTH, β- and γ-lipotropin, α-, β -, and γ -MSH (melanocyte-stimulating hormone), CLIP (corticotropin like intermediary peptide), -endorphin, and Met-enkephalin. The points of cleavage are paired basic residues, Arg–Lys, Lys–Arg, or Lys–Lys.
The concentration of peptide hormones within se cretory granules is so high that the vesicle contents are virtually crystalline; when the contents are released by exocytosis, a large amount of hormone is released suddenly. The capillaries that serve peptide-producing endocrine glands are fenestrated (and thus permeable to peptides), so the hormone molecules readily enter the bloodstream for transport to target cells elsewhere. As noted earlier, all peptide hormones act by binding to receptors in the plasma membrane. They cause the generation of a second messenger in the cytosol, which changes the activity of an intracellular enzyme, thereby altering the cell’s metabolism.
The water-soluble compounds epinephrine (adrenaline) and norepinephrine (nor adrenaline) are catecholamines, named for the structurally related compound catechol. They are synthesized from tyrosine.
Tyrosine→ L-DOPA→ Dopamine→ Norepinephrine→ Epinephrine
Catecholamines produced in the brain and in other neural tissues function as neurotransmitters, but epinephrine and norepinephrine are also hormones, synthesized and secreted by the adrenal glands. Like the peptide hormones, catecholamines are highly concentrated within secretory vesicles and released by exocytosis, and they act through surface receptors to generate intracellular second messengers. They mediate a wide variety of physiological responses to acute stress . Eicosanoids The eicosanoid hormones (prostaglandins, thromboxanes, and leukotrienes) are derived from the 20-carbon polyunsaturated fatty acid arachidonate.
Unlike the hormones described above, they are not synthesized in advance and stored; they are produced, when needed, from arachidonate enzymatically released from membrane phospholipids by phospholipase A2 . The enzymes of the pathway leading to prostaglandins and thromboxanes are very widely distributed in mammalian tissues; most cells can produce these signals, and cells of many tissues can respond to them through specific plasma membrane receptors. The eicosanoid hormones are paracrine hormones, secreted into the interstitial fluid (not primarily into the blood) and acting on nearby cells. Prostaglandins promote the contraction of smooth muscle, including that of the intestine and uterus (and can therefore be used medically to in duce labor). They also mediate pain and inflammation in all tissues. Many antiinflammatory drugs act by inhibiting steps in the prostaglandin synthetic pathway . Thromboxanes regulate platelet function and therefore blood clotting. Leukotrienes LTC4 and LTD4 act through plasma membrane receptors to stimulate contraction of smooth muscle in the intestine, pulmonary airways, and trachea. They are mediators of the severe immune response called anaphylaxis.
The steroid hormones (adrenocortical hormones and sex hormones) are synthesized from cholesterol in several endocrine tissues.
They travel to their target cells through the blood stream, bound to carrier proteins. More than 50 corti costeroid hormones are produced in the adrenal cortex by reactions that remove the side chain from the D ring of cholesterol and introduce oxygen to form keto and hydroxyl groups. Many of these reactions involve cytochrome P-450 enzymes . The steroid hormones are of two general types. Glucocorticoids (such as cortisol) primarily affect the metabolism of carbohydrates; mineralocorticoids (such as aldosterone) regulate the concentrations of electrolytes in the blood. Androgens (testosterone) and estrogens are synthesized in the testes and ovaries. Their synthesis also involves cytochrome P-450 enzymes that cleave the side chain of cholesterol and introduce oxygen atoms. These hormones affect sexual development, sexual behavior, and a variety of other re productive and nonreproductive functions. All steroid hormones act through nuclear receptors to change the level of expression of specific genes (p. 465). Recent evidence indicates that they also have more rapid effects, mediated by receptors localized in the plasma membrane.
Calcitriol (1,25-dihydroxycholecalciferol) is produced from vitamin D by enzyme catalyzed hydroxylation in the liver and kidneys (see Fig. 10–20a).
Vitamin D is obtained in the diet or by photolysis of 7 dehydrocholesterol in skin exposed to sunlight. Calcitriol works in concert with parathyroid hormone in Ca2+ homeostasis, regulating [Ca2+] in the blood and the balance between Ca2+ deposition and Ca2+ mobilization from bone. Acting through nuclear receptors, calcitriol activates the synthesis of an intestinal Ca2+ binding protein essential for uptake of dietary Ca2+. In adequate dietary vitamin D or defects in the biosynthesis of calcitriol result in serious diseases such as rickets, in which bones are weak and malformed .
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).
All tissues are retinoid targets, as all cell types have at least one form of nuclear retinoid receptor. In adults, the most significant targets include cornea, skin, epithelia of the lungs and trachea, and the immune system. RA regulates the synthesis of proteins essential for growth or differentiation. Excessive vitamin A can cause birth defects, and pregnant women are advised not to use the retinoid creams that have been developed for treatment of severe acne.
The thyroid hormones T4 (thyroxine) and T3 (triiodothyronine) are synthesized from the pre cursor protein thyroglobulin (Mr 660,000). Up to 20 Tyr residues in thyroglobulin are enzymatically iodinated in the thyroid gland, then two iodotyrosine residues con dense to form the precursor to thyroxine. When needed, thyroxine is released by proteolysis. Condensation of monoiodotyrosine with diiodotyrosine produces T3, which is also an active hormone released by proteolysis.
The thyroid hormones act through nuclear receptors to stimulate energy-yielding metabolism, especially in liver and muscle, by increasing the expression of genes en coding key catabolic enzymes.
Nitric oxide is a relatively stable free radical synthesized from molecular oxygen and the guanidino nitrogen of arginine in a reaction catalyzed by NO synthase.
This enzyme is found in many tissues and cell types: neurons, macrophages, hepatocytes, myocytes of smooth muscle, endothelial cells of the blood vessels, and epithelial cells of the kidney. NO acts near its point of release, entering the target cell and activating the cytosolic enzyme guanylyl cyclase, which catalyzes the formation of the second messenger cGMP.
