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Chapter 3
Synthesis, Metabolism, and
Actions of Bioregulators
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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).
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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.
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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.
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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).
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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.
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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.
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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.
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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 epinephrine’s actions through PKA in other tissues is provided
in Figure 3-12.
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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.
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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.
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Figure 3-11 G-protein interactions and inhibition of cellular reactions. Growth hormone (GH)-releasing
hormone binds to its receptor (R1) and activates the Gs-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 R2 receptor, works through an inhibitory Gi-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, 1986. © The Endocrine Society.)
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Figure 3-12 IP3 and DAG as second messengers. Schematic representation of the action of a chemical
regulator working through a Gq-protein to activate the enzyme phopholipase C (PLC) and generating the second
messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol bisphosphate (PIP2).
IP3 releases intracellular Ca2+, 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.
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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.
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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).
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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 hormone’s
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.
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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-theScience of Endocrine Disruptors,” World Health Organization, Geneva, Switzerland, 2002, p. 20.)
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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.
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Figure 3-18 (A) C18 estrogens and (B) C19 androgens.
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Figure 3-19 (A) Some C21 corticosteroids and (B) C21 progestogens.
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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.
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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.
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Figure 3-22 Synthesis pathway for progesterone.
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Figure 3-23 Synthesis of corticosteroids from progesterone.
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Figure 3-24 4- 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.
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Figure 3-25 Synthesis of estrogens from androgens. Estrogen synthesis requires either prior synthesis of an
androgen or an external source of androgen.
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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).
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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.)
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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.
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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.
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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.)
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Figure 3-31 Thyroxine, precursors, and some deiodinated metabolites. Synthesis of MIT, DIT, T4, and
conversion of T4 to T3 and rT3 by thyroid deiodinase enzymes (see text and Figure 3-32 for details).
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Figure 3-32 Roles of thyroid peroxidase (TPO) in thyroxine (T4) 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, T4) leaving behind a modified alanine called dehyroalanine.
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Figure 3-32 cont’d. Roles of thyroid peroxidase (TPO) in thyroxine (T4) 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, T4) leaving behind a modified alanine called dehyroalanine.
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Figure 3-33 Genomic mechanism of action for triiodothyronine (T3). 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 T3 in the cytosol
prior to binding with the TR.
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Figure 3-34 Additional thyroid hormone metabolites. See text for explanation.
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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.,
PGF2α, PGE1).
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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.)
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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.
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