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Chapter 3 Chapter 3 Synthesis, Metabolism, and Actions of Bioregulators Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-1 Synthesis of catecholamines. Catecholamines may be synthesized from either of the amino acids phenylalanine or tyrosine. The rate-limiting enzyme for this pathway is tyrosine hydroxylase. Depending upon which enzymes are active in a cell, the final secretory product may be dopamine, norepinephrine, or epinephrine. A catechol group consists of a benzene ring with two adjacent hydroxyl groups attached (highlighted). 2 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-2 Synthesis of indolamines: serotonin and melatonin. 5-HIAA is a principal metabolite of serotonin and 6-hydroxymelatonin is the principal metabolite of melatonin. The rate-limiting enzyme for melatonin synthesis is N-acetyltransferase (NAT). Abbreviations: AADC, aromatic-Lamino acid decarboxylase; HIOMT, hydroxyindole-O-methyltransferase; MAO, monoamine oxidase; TryptH, tryptophan hydroxylase. 3 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-3 Synthesis of export peptides. (A) The product of mRNA produced at the ribosome is the preprohormone. The signal peptide is necessary to connect the prohormone to the endoplasmic reticulum and is cut off from the prohormone, which then enters the cisternae of the endoplasmic reticulum. The prohormone is later cleaved to produce an inactive fragment and the definitive hormone. Typically, both the inactive fragment and the hormone will be released from the cell. Sometimes the entire prohormone may be released, as well. (B) The hormone insulin is synthesized from the preprohormone by first removing the signal peptide, folding the single peptide chain of the prohormone and cleaving it in two places to yield a connecting C-peptide fragment and the hormone insulin that now appears to be made of two separate polypeptide chains. Some proinsulin is secreted along the the C-peptide and insulin. (C) Five copies of the TRH tripeptide are produced by multiple cleavages of each prohormone. 4 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-4 Colorized representations of the insulin peptides (amino terminus in blue, carboxy terminus in red). Disulfide bonds are indicated by the thick black lines. Peptides are modeled after protein data base structures (human pro-insulin, code 2KQP; human T insulin, code 1MSO; human relaxin, code 6RLX; human IGF-I, code 1BQT; human IGF-II, 1IGL). 5 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-5 Ligand/receptor fit. As occurs for enzymes and substrates, ligands bind to particular domains on receptor molecules and typically cause conformational changes in the receptor that are important for initiating a response in a target cell. This hypothetical illustration imagines a ligand that binds to a receptor with tyrosine kinase activity. Once occupied, the receptor changes shape and now interacts with ATP and a protein kinase. The protein kinase is activated by phosphorylation and can now produce other effects in the cell. The receptor releases its ligand for degradation and returns to its unoccupied state. Alternatively, the ligand–receptor complex may be internalized prior to release of ligand and/or degrading of the receptor. 6 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-6 Transmembrane receptors. (A) A tyrosine kinase receptor has a ligand-binding extracellular domain, a single transmembrane domain, and an intracellular domain that acts as a tyrosine kinase. (B) A G-protein-coupled receptor (GPCR) also has three domains. The extracellular domain is responsible for binding the specific ligand. The transmembrane domain traverses the membrane seven times before ending in the cytoplasmic domain that is coupled with a G-protein. The type of G-protein is dependent upon the type of receptor. Occupied receptors often form dimmers prior to activation of intracellular events. 7 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-7 Formation and degradation of cAMP. ATP is converted by adenylyl cyclase to cAMP. One of several phosphodiesterases (see Table 3-8) inactivates cAMP by converting it to ordinary AMP. 8 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-8 Actions of cAMP within target cell. After binding to its cell membrane β-adrenergic receptor, the ligand, epinephrine, produces different effects in target cells by first stimulating production of cAMP, which converts inactive protein kinase A (PKA) to active PKA*. In liver and skeletal muscle, PKA phosphorylates the enzyme glycogen synthetase, converting it from an active to an inactive form and thus reducing glycogen synthesis (not shown). PKA* converts inactive enzyme phosphorylase b through an additional phosphorylation to its active form (Phosphorylase a*) and causes hydrolysis of glycogen to release glucose-1-phosphate (G1P), which in liver can be converted to free glucose and free phosphate (P). Free glucose leaves the cell via mediated transport. AC, adenylyl cyclase. A comparision of epinephrines actions through PKA in other tissues is provided in Figure Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-9 G-proteins consist of three subunits. The -subunit that has innate GTP-binding and hydrolyzing capacity can separate from the other subunits following interaction with an appropriate, occupied receptor. The free -subunit interacts with a membrane channel protein or an enzyme that generates a second messenger. Once the GTP has been hydrolyzed, the subunits recombine. 10 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-10 Subsequent actions of PKA following epinephrine activation in different tissues. Abbreviations: HSL, hormone-sensitive lipase; NEFAs, non-esterified fatty acids; TAGs, triacylglycerides or fats; phospholamban is an inhibitor of calcium pumps. 11 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-11 G-protein interactions and inhibition of cellular reactions. Growth hormone (GH)-releasing hormone binds to its receptor (R 1 ) and activates the G s -protein that turns on adenylyl cyclase (AC) to synthesize cAMP from ATP. cAMP acts as a second messenger to mediate release of GH. Somatostatin (SST), after binding to the R 2 receptor, works through an inhibitory G i -protein to prevent the activation of AC. Thus, in the presence of SST, it is difficult to stimulate GH release except through the addition of exogenous cAMP. A similar mechanism operates in the antagonism of norepinephrine by acetylcholine in cardiac muscle. (Adapted with permission from Frohman, L.A. and Jansson, J.O., Endocrine Reviews, 7, 223–253, © The Endocrine Society.) 12 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-12 IP 3 and DAG as second messengers. Schematic representation of the action of a chemical regulator working through a G q -protein to activate the enzyme phopholipase C (PLC) and generating the second messengers inositol trisphosphate (IP 3 ) and diacylglycerol (DAG) from phosphatidylinositol bisphosphate (PIP 2 ). IP 3 releases intracellular Ca 2+, which may interact with secretory vesicles and induce exocytosis of some product (e.g., hormone, secretory protein). DAG may activate phosphokinase C (PKC*) and produce additional phosphorylations and various effects. 13 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-13 Downregulation of occupied receptors and receptor recycling. Occupied epidermal growth factor receptors (EGFRs) and G-protein-coupled receptors migrate along the cell membrane to locations where endosomes form (via endocytosis). These sites may be associated with the special proteins such as clathrin. The early sorting endosomes direct the fates of the internalized receptors, with some directed to late endosomes, which fuse with lysosomes to form endolysosome, usually resulting in degradation of both ligand and most or all of the receptors. Some receptors may be directed to recycling endosomes, and the receptors are recycled directly to the cell surface. 14 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-14 The kinase cascade induced by a tyrosine kinase receptor. Occupied receptors interact with a series of protein kinases resulting in production of transcription factors (TFs), which as third messengers enter the nucleus and alter transcription. See text for an explanation of the abbreviations. The cascade can also be activated by cross-talk (see Figure 3-17). 15 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-15 Cross-talk between intracellular hormone actions. Hormone A binds to an ion channel receptor that regulates ion influx. Hormone B binds to a GPCR that operates through a G s second-messenger system. Hormone C binds to a tyrosine kinase receptor that activates a protein kinase complex (PK) that initiates a kinase cascade ending with MAPK activation of a transcription factor. Red arrows represent each hormones mechanism of action. Black arrows represent possible cross-talk effects on the mechanisms of the other hormones affecting this cell. Such interactions could by stimulatory or inhibitory in nature. X represents unidentified intermediate steps. 16 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-16 Another kind of cross-talk. This diagram illustrates some of the ways in which bioregulators communicate with other pathways such that one bioregulator system may influence the effectiveness of another. See Appendix A for abbreviations. (Adapted from Damstra, T. et al., Global Assessment of the State-of-the- Science of Endocrine Disruptors, World Health Organization, Geneva, Switzerland, 2002, p. 20.) 17 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-17 The steroid nucleus. (A) There are 17 carbons in the nucleus with two additional carbons (18, 19) attached to carbons 13 and 10, respectively. The four rings of the nucleus are labeled A, B, C, and D. The side chain of carbons 20 to 27 is attached to the steroid nucleus at carbon 17 in the -configuration and is indicated as a solid line. Some of the asymmetric carbons of the nucleus are designated as enlarged dots where the lines representing the covalent bonds intersect. (B) Atoms attached to an asymmetric carbon in the -configuration are designated with a dashed line as indicated for 5 OH. Those attached in the -configuration (including carbons 18 and 19) are indicated with a solid wedge. 18 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-18 (A) C 18 estrogens and (B) C 19 androgens. 19 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-19 (A) Some C 21 corticosteroids and (B) C 21 progestogens. 20 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-20 Some synthetic steroids and nonsteroids with steroid-like activity. (A) Genistein is a phytoestrogen found in clover and other plants. (B) Diethylstilbestrol is a potent estrogen. (C) Dexamethasone is a synthetic glucocorticoid that contains fluorine and is more potent than any of the naturally occurring ones. (D) Cyanoketone is a steroid that inhibits the enzyme that normally converts the steroid pregnenolone to progesterone. (E) Cyproterone acetate is an antiandrogen and blocks androgen binding to receptors. (F) Mifepristone, or RU 486, is an antiprogesterone and an antiglucocorticoid. (G) Diethyl-hexylphthalate (DEHP) has effects on several HP axes. (H) Glycyrrhetinic acid is found in licorice and has weak corticosteroid activity. (I, K) Selective estrogen receptor modulators (SERMs) roloxifene and tamoxifen. (J) Trenbolone, a potent synthetic androgen. (L) Bisphenyl A (BPA), an estrogenic chemical. 21 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-21 Hypothetical steroids employed in steroid nomenclature. These compounds do not exist and are used only for the purposes of constructing the chemical names for the four major groups of steroid hormones. 22 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-22 Synthesis pathway for progesterone. 23 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-23 Synthesis of corticosteroids from progesterone. 24 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure and 5 -pathways for androgen synthesis. The 5 -pathway typically occurs in the adrenal cortex and usually stops with the production of DHEA or DHEAS. In ovaries of some species, this pathway may lead to testosterone and eventually to estrogen synthesis. Testes employ only the 4 -pathway (highlighted). Note that the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) can convert several 5 - steroids into 4 -steroids. 25 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-25 Synthesis of estrogens from androgens. Estrogen synthesis requires either prior synthesis of an androgen or an external source of androgen. 26 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-26 Genomic mechanism of activation by steroids. The interaction of steroids with different genes in a target cell may direct the synthesis of structural proteins such as cytoskeletal elements or receptors as well as enzymes. These enzymes may produce a variety of effects within the cell. The genomic mechanism of action for thyroid hormones is very similar, with the emphasis more on nuclear location of unoccupied receptors. Additionally, occupied thyroid hormone receptors form heterodimers with RXR receptors (see Figure 3-33). 27 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-27 Steroid-activated transcription factors and genomic actions. In this example, unoccupied progesterone receptor is associated with several molecular chaperones including several heatshock proteins. Once occupied, the receptors are phosphorylated, lose some of their heatshock proteins, translocate to the nucleus, and form homodimers. Following binding of the receptor dimer to the HRE (PRE) site on nuclear DNA, a second phosphorylation occurs and an adapter protein complex is recruited that facilitates interaction with the general transcription apparatus. RNA polymerase activity and hence transcription are thereby modulated. Other steroids work in a similar manner. Thyroid hormone also operates this way; however, it forms heterodimers in the nucleus prior to binding to the TRE on DNA (see Figure 3-33). (Adapted with permission from McDonnell, D.P., Trends in Endocrinology and Metabolism, 6, 133–138, 1995.) 28 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-28 Zinc fingers. Certain sequences of amino acids can fold around zinc (Zn) ions to form projections called zinc fingers. These zinc fingers are associated with the DNA-binding domains of steroid receptors and facilitate binding to HREs on the DNA. Only a monomer is depicted here. P, phosphate. 29 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-29 Steroids and synthetically related lipid bioregulators. Formation of dimer ligand–receptor complexes involves heterodimer formation with the exception of the vertebrate steroids that form only homodimers prior to activating gene response elements. Dimers are indicated in brackets. See Appendix A or text for explanation of abbreviations. 30 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-30 Some nonconjugated steroid metabolites. (Adapted with permission from Norman, A. and Litwack, G., Hormones, 2nd ed., Academic Press, San Diego, CA, 1997, p. 84.) 31 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-31 Thyroxine, precursors, and some deiodinated metabolites. Synthesis of MIT, DIT, T 4, and conversion of T 4 to T 3 and rT 3 by thyroid deiodinase enzymes (see text and Figure 3-32 for details). 32 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-32 Roles of thyroid peroxidase (TPO) in thyroxine (T 4 ) synthesis. (A) Tyrosine molecules are incorporated into the polypeptide backbone of thyroglobulin. (B) The enzyme TPO converts iodide to active iodide. (C) TPO then attaches the active iodides to the phenolic ring of the tyrosines to form diiodothyronines (DITs). (D) TPO removes the hydroxyphenyl group from one DIT to another to form a thyronine (3,3´,5,5´- tetaiodothyronine, T 4 ) leaving behind a modified alanine called dehyroalanine. 33 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-32 contd. Roles of thyroid peroxidase (TPO) in thyroxine (T 4 ) synthesis. (A) Tyrosine molecules are incorporated into the polypeptide backbone of thyroglobulin. (B) The enzyme TPO converts iodide to active iodide. (C) TPO then attaches the active iodides to the phenolic ring of the tyrosines to form diiodothyronines (DITs). (D) TPO removes the hydroxyphenyl group from one DIT to another to form a thyronine (3,3´,5,5´- tetaiodothyronine, T 4 ) leaving behind a modified alanine called dehyroalanine. 34 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-33 Genomic mechanism of action for triiodothyronine (T 3 ). Typically, unoccupied thyroid hormone receptors (TRs) are localized in the nucleus and once occupied form heterodimers with RXRs prior to binding to the thyroid response element (TRE) in the target gene. Thyroxine (T 4 ) typically is converted to T 3 in the cytosol prior to binding with the TR. 35 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-34 Additional thyroid hormone metabolites. See text for explanation. 36 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-35 Prostaglandin structures. The basic chemical formula for the prostaglandins is that of prostanoic acid. These C20-lipids are divided into classes (A, B, F, etc.) based on substitutions to the fivemembered carbon ring. Modifications of the side chains result in different forms within a class, each designated by a subscript (e.g., PGF 2α, PGE 1 ). 37 Copyright © 2013 Elsevier Inc. All rights reserved.
Figure 3-36 Eicosanoid synthesis. The precursor for all eicosanoids, arachidonic acid, can be synthesized from diacylglycerol (DAG) which has dual roles as second messenger and eicosanoid precursor. NSAIDs (nonsteroidal antiinflammatory drugs) and ETYA (eicosatetraynoic acid) inhibit the enzyme cyclooxygenase and block prostaglandin and thromboxane synthesis. ETYA and NDGA (nordihydroguaiaretic acid) block the enzyme 5-lipoxygenase and prevent leukotriene synthesis. EYTA is a modified form of arachidonic acid that competes for any enzyme that normally uses arachidonic acid as its substrate. (Adapted with permission from Bolander, F.F., Molecular Endocrinology, Academic Press, San Diego, CA, 1989.) 38 Copyright © 2013 Elsevier Inc. All rights reserved.
Box Figure 3B-1 Dioxin actions. Dioxins bind to the arylhydrocarbon receptor (ahR). The ligand–receptor complex enters the nucleus and dimerizes with the aryl hydrocarbon nuclear translocator protein (ARNT) and activates the CYP1A1 gene. This gene produces a metabolizing enzyme that destroys a variety of potential toxicants including dioxins. 39 Copyright © 2013 Elsevier Inc. All rights reserved.
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