Biochemistry Hormones PDF

BIOCHEMISTRY | BLOCK 2.2 Part I: Hormones Dr. Celina Vilches | September 12, 2022 | 7:30 – 9:30 AM Transcribed by: Balbuena, Barranco, Bulcase, Canapit OUTLINE...

BIOCHEMISTRY | BLOCK 2.2 Part I: Hormones Dr. Celina Vilches | September 12, 2022 | 7:30 – 9:30 AM Transcribed by: Balbuena, Barranco, Bulcase, Canapit OUTLINE Old Concept - Hormone/s of single cell type and 1. Concepts on Endocrine System few kinds of cell elicit a unique a. Hormones response. b. Target Organs Modern Concept c. Receptors - Hormone/s of single cell type and 2. Diversity of the Endocrine System several cell types can elicit a a. Steroid Hormones, Amines Hormones, positive or negative response. Polypeptide and Protein Hormones b. Classification of Hormones PHYSIOLOGICALLY RELEVANT HORMONE – RECEPTOR INTERACTION CELLULAR RESPONSE Features: Binding is specific. Stimulus from immediate environment - Influenced by the presence of an - Extracellular matrix antagonist or an agonist. - Cellular attachment Binding should be saturable. Distant sources of stimulus Binding should occur within the concentration - Soluble extracellular molecules range of the expected biochemical response. EXTRACELLULAR MOLECULES FACTORS THAT WILL INFLUENCE TARGET ORGAN RESPONSE TO THE HORMONE HORMONES Derived from a Greek term that means “to CONCENTRATION OF THE HORMONE arouse activity”. Substance that is synthesized in one organ and transported by the circulatory system to act on 1. The rate of synthesis and secretion of the another tissue. hormones. Paracrine 2. The proximity of the target cell to the hormone - Can act on the adjacent cells. source (dilution effect). Autocrine 3. The affinity (dissociation constant; Kd) of the - Can act on the cell in which they hormone with specific plasma transport proteins were synthesized without entering (if any). the systemic circulation. 4. The conversion of inactive or suboptimally active forms of the hormone into the fully active form. TARGET ORGANS 5. The rate of clearance of hormone from plasma, Any cell which contains a receptor wherein a by other tissues, or by digestion, metabolism, or hormone can bind to it. The binding may or may not excretion. elicit a response. 1 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT DETERMINANTS OF THE TARGET CELL RESPONSE RECEPTORS ARE PROTEINS 1. The number, relative activity, and state of INSULIN RECEPTOR occupancy of the specific receptors on the Is a heterotetramer composed of two copies of plasma membrane or in the cytoplasm or two different protein subunits (α2β2) linked by nucleus. multiple disulfide bonds in which the 2. The metabolism (activation or inactivation) of extracellular α subunit binds insulin and the the hormones in the target cell. membrane-spanning β subunit transduces the 3. The presence of other factors within the cell signal through the tyrosine protein kinase that is necessary for the hormone response. domain located in the cytoplasmic portion of 4. Up- or down-regulation of the receptor this polypeptide. consequent to the interaction with its ligand. 5. Post-receptor desensitization of the cell, INSULIN-LIKE GROWTH FACTOR I (IGF-I) AND including down-regulation of the receptor. EPIDERMAL GROWTH FACTOR (EGF) RECEPTORS Generally similar in structure to the insulin RECEPTORS receptor. GROWTH HORMONE AND PROLACTINE RECEPTORS Cell associated recognition molecules in the Also span the plasma membrane of target cells target organs. but do not contain intrinsic protein kinase Hormone-Receptor Interaction activity. Binding will result in initiation of hormone Ligand binding to these receptors, however, activity. results in association and activation of a Dissociation will result in termination of completely different protein kinase signaling hormone activity. pathway, the JakStat pathway. It is a protein. It has a dynamic quality. POLYPEPTIDE AND PROTEIN HORMONES AND CATECHOLAMINE RECEPTORS Transduce signals by altering the rate of production of cAMP through G proteins, are characterized by the presence of seven domains that span the plasma membrane. Receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family currently have no known ligand and thus are called Contain at least 2 functional domains: orphan receptors. Receptor domain – Site in the receptor Nuclear receptor superfamily plays a critical where hormone recognition and binding role in the regulation of gene transcription by occurs. hormones. Coupling domain – Generates signals that couples hormone recognition to some intracellular function. 2 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT  COMPARISON BETWEEN RECEPTORS AND - The skin, liver and kidney are TRANSPORT PROTEINS required for the production of calcitriol. DIVERSITY OF THE ENDOCRINE SYSTEM Most precursor is produced by the malphigian layer of the epidermis from 7-dehydrocholesterol in an Hormones are synthesized in a variety of cellular arrangements. ultraviolet light mediated reaction Hormones are chemically diverse. Hormones are synthesized and modified for full Vit. D binding protein binds Vit. D from the skin or GIT activity in variety of ways. undergo 25 hydroxylation (obligatory process) in the HORMONES ARE SYNTHESIZED IN A VARIETY OF ER to produce 25(OH)2D. CELLULAR ARRANGEMENTS 25(0H)2D undergoes hydroxylation at C1 position in Synthesized in discrete organs the mitochondria of the proximal convoluted tubule Designed solely for this specific purpose and become biologically active. - Thyroid glands – triiodothyronine - Adrenals – glucocorticoids and HORMONES ARE CHEMICALLY DIVERSE mineralocorticoids - Pituitary – TSH, FSH, LH, GH, PRL, Synthesized from a wide variety of chemical ACTH building blocks Designed to perform 2 related functions Cholesterol - Ovaries – produce mature oocytes Glucocorticoids; Mineralocorticoids; and the reproductive hormones Estrogens; Progestens, Calcitriols. estradiol and progesterone. Some steroid hormones can act as - Testes – produce mature precursor to another hormone. spermatozoa and testosterone. - Progesterone Glucocorticoids Specialized cells within the organ Large series is derived from cholesterol. - Pancreas – beta cells – insulin - Glucocorticoids - Kidney – angiotensin II - Mineralocorticoids - Thyroid – parafollicular cells (C - Androgens cells) – calcitonin - Estrogens Require parenchymal cells of more than 1 organ - Progestins Calcitriol (1,25(OH)2-D3) - 1,25(OH)2-D3 - Derived from Cholesterol 3 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT  Amino acids Tyrosine Catecholamines, Thyroid hormones Norepinephrine Polypeptides or Glycoproteins - Produced by sympathetic nerves Vary in sizes - 80% is made in situ Tripeptides TRH Multiple amino acids (GH; 191 amino acids) Heterodimers Insulin (AB chain) HORMONES ARE SYNTHESIZED AND MODIFIED FOR FULL ACTIVITY IN VARIETY OF WAYS Synthesized in their final form and secreted immediately. - Hormones derived from Cholesterol. Clinical Application Synthesized in their final form and stored in the Parkinson’s Disease producing cell. - Catecholamines cannot cross the Synthesized from precursor molecule in the blood brain barrier. producing cell then are processed and secreted - Deficiency of dopamine synthesis. upon physiologic cue. - Treatment: - Insulin ▪ L-dopa → Dopamine (Catalyzed by Dopa-decarboxylase) Converted to active forms in the periphery. α – Methyldopa - T3 Act as competitive inhibitor. Anti-hypertensive. AMINE HORMONES T3 AND T4 SYNTHESIS Requires an element for bioactivity - Iodine Synthesized as part of a very large precursor molecule - Thyroglobulin Stored in an intracellular reservoir - Colloid Peripheral conversion - T4→T3 CATECHOLAMINES Dopamine, Epinephrine & Norepinephrine Synthesized from tyrosine in the chromaffin cells of the adrenal medulla. Epinephrine - 80% in the adrenal medulla 4 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT  A. Structure of insulin. B. Formation of human insulin from preproinsulin. S-S = disulfide bond. PEPTIDE HORMONES PARATHYROID HORMONE SEVERAL HORMONES ARE MADE FROM LARGER PEPTIDE PRECURSORS INSULIN Synthesized as a preprophormone (MW: 11,500), which is the prototype for peptides that are Secreted as an 84-Amino-Acid Peptide. processed from larger precursor molecules Biosynthesis of PTH and its subsequent secretion are regulated by the plasma ionized calcium (Ca2+) concentration. Acute decrease of Ca2+ results in a marked increase of PTH mRNA, and this is followed by an increased rate of PTH synthesis and secretion. ANGIOTENSIN II Renin-angiotensin system is involved in the regulation of blood pressure and electrolyte metabolism (through production of aldosterone). Insulin and C-peptide molecules are connected at two sites by dipeptide links. An initial cleavage by a trypsin-like enzyme (open arrows) followed by several cleavages by a carboxypeptidase-like enzyme (solid arrows) results in the production of the heterodimeric (AB) insulin molecule (colored) and the C-peptide (white). FORMATION, METABOLISM, AND SELECTED PHYSIOLOGIC ACTIVITIES OF ANGIOTENSINS 5 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITOR Nonapeptide analogs of angiotensin I and other compounds act as competitive inhibitors of converting enzyme and are used to treat renin- dependent hypertension. PRO-OPIOMELANOCORTIN (POMC) PEPTIDE FAMILY POMC family consists of peptides that act as hormones (ACTH, LPH, MSH) and others that may serve as neurotransmitters or neuromodulators (endorphins). ADRENOCORTICAL HORMONES Synthesized as a precursor molecule of 285 amino acids and is processed differently in various regions Mineralocorticoids of the pituitary. Glucocorticoids Androgens ADRENAL STEROIDOGENESIS The adrenal steroid hormones are mostly derived from the plasma, but a small portion is synthesized in situ from acetyl-CoA via mevalonate and squalene. Cholesterol in the adrenal is esterified and There are three basic peptide groups: (1) ACTH, which stored in cytoplasmic lipid droplets. can give rise to α-MSH and corticotropin-like Upon stimulation of the adrenal by ACTH, an intermediate lobe peptide (CLIP); (2) β-lipotropin (β- esterase is activated, and the free cholesterol LPH), which can yield γ-LPH, β-MSH, and β-endorphin formed is transported into the mitochondrion, (and thus α- and γ-endorphins); and (3) a large amino where a cytochrome P450 side chain cleavage terminal peptide, which generates γ-MSH. enzyme (P450scc) converts cholesterol to pregnenolone. STEROID HORMONES Cleavage of the side chain involves sequential hydroxylations, first at C22 and then at C20. Synthesized from cholesterol and are not stored. ACTH-dependent steroidogenic acute Steroids are highly lipid soluble, once they are regulatory (StAR) protein is essential for the synthesized, they simply diffuse across the cell transport of cholesterol to P450scc in the inner membrane and enter the interstitial fluid and mitochondrial membrane. then the blood. All mammalian steroid hormone are formed from cholesterol via pregnenolone. - Occur either in the mitochondrial or in the ER. 6 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT  Exhibits cellular specificity Steroidogenesis thus involves the repeated - Mineralocorticoid synthesis → Zona shuttling of substrates into and out of the Glomerulosa mitochondria. - Glucocorticoid synthesis → Zona fasciculata and reticularis. ANDROGEN SYNTHESIS MINERALOCORTICOID SYNTHESIS Major androgen precursor ‘ Dehydroepiandrosterone (DHEA) ALDOSTERONE - Produced by the adrenal cortex Zona Glomerulosa Androstenedione - more potent androgen Pregnenolone → Progesterone formed in the adrenal by the action of the lyase 2 sER enzymes on 17α-hydroxyprogesterone. Hydroxysteroid dehydrogenase Testosterone - result as a reduction of Δ5,4 isomerase androstenedione at the C17 position the most Process involved Hydroxylation potent adrenal androgen. Cortisone → 18hydroxylase → Aldosterone Small amounts of testosterone are produced in Aldosterone synthase the adrenal by this mechanism, but most of this This unique distribution of enzymes and the conversion occurs in the testes. special regulation of the zona glomerulosa by K Follows the glucocorticoid pathway + and angiotensin II have led some Increased Adrenal Androgen production investigators to suggest that, in addition to the Glucocorticoid biosynthesis is adrenal being two glands, the adrenal cortex is impeded actually two separate organs. Adrogenital syndrome GLUCOCORTICOID SYNTHESIS TESTICULAR STEROIDOGENESIS Requires 3 hydroxylases located in zona fasciculata and reticularis. Testicular androgens Hydroxylation of C11 is slow. Synthesized in the interstitial tissue by Should occur last, if it occurs first then the Leydig cells mineralocorticoid pathway is followed. precursor → Cholesterol Hydroxylation of C17 Rate limiting step is the delivery of Fast; Enzyme 17α-hydroxylase cholesterol to the inner mitochondrial sER enzyme membrane Progesterone/Pregnenolone StAR (substrate) Reaction is promoted by LH Pregnenolone → hydroxylated at C17 → 17a hydroxyprogesterone → Hydroxylated at C21 OVARIAN STEROIDOGENESIS → 11 deoxycortisol -→ hydroxylated at C11 → Cortisol 17B-estradiol is the primary estrogen of 3 Enzymes involved ovarian origin 17α-hydroxylase In pregnancy → estriol→ placenta 11β-Hydroxylase Estrogen are formed by aromatization of Mitochondrial enzyme androgens 21 Hydroxylase 7 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT  Clinical implication Aromatase Inhibitors inhibits CLASSIFICATION OF HORMONES Estrogen formation Use as chemo drugs for Hormones can be classified according to: breast cancer Chemical composition Post-menopausal women Solubility properties Conversion of andostenedione Location of receptors → estrone Nature of the signal used to mediate hormonal Major source of estrogen action within the cell. Aromatase activity is present in the adipose cells, liver, skin other tissues GENERAL CLASSIFICATION OF HORMONES Obesity → breast Ca Liver diseases, Hyperthyroidism, Aging, Obesity Increased aromatase activity “Estrogenization”. COMPARISON OF PEPTIDE, STEROID AND AMINO ACID-DERIVATIVE HORMONES CLASSIFICATION OF HORMONES AS TO ITS SOLUBILITY A. LIPID-SOLUBLE HORMONES (GROUP I) Hormones in group I are lipophilic. Associated with plasma transport or carrier proteins, a process that circumvents the problem of solubility. DIVERSITY IN THE STORAGE OF HORMONES Prolonging the plasma half- life of the hormone. Relative percentages of bound and free hormone are determined by the amount, binding affinity, and binding capacity of the transport protein Free hormones encounter receptors in either the cytosol or nucleus of target cells. FREE HORMONE Biologically active form Readily traverses the lipophilic plasma membrane of all cells 8 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT  These second messengers affect gene transcription and influence a variety of other biological processes. G-PROTEIN COUPLED RECEPTORS Group II hormones bind to receptors that couple to effectors through a guanine-binding protein (G-proteins) intermediary. Receptors of this class, which signal through G- proteins, are known as G-protein–coupled receptors (GPCRs). Encounters receptors in either the cytosol or nucleus of target cells Ligand-receptor complex is the intracellular messenger in this group B. WATER-SOLUBLE HORMONES (GROUP II) PEPTIDE & CATECHOLAMINE cAMP IS THE INTRACELLULAR SIGNAL FOR MANY Many hormones are water-soluble. RESPONSES Have no transport proteins Cyclic AMP was the first intracellular second Have a short plasma half-life messenger signal identified in mammalian cells. Initiate a response by binding to a receptor Several components comprise a system for the located in the plasma membrane generation, degradation, and action of cAMP. Uses intracellular signals for their mechanism of action; cAMP (cyclic AMP, 3′,5′-adenylic acid). C. GROUP II.A Cells communication is dependent on intracellular metabolic processes through intermediary molecules called second Second messenger concept arose from an messengers (the hormone itself is the first observation that epinephrine binds to the plasma messenger). membrane of certain cells and increases Synthesis of second messengers (Ca2+; and intracellular cAMP. phosphatidylinositides) is triggered by the presence of the primary hormone (molecule) Series of experiments confirmed that cAMP binding its receptor. mediate the effects of many hormones. 9 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT  SUBCLASSIFICATION OF GROUP II.A D. GROUP II.B Atrial natriuretic factor (ANF) uses cGMP as its second messenger. E. GROUP II.C Several hormones, many of which were previously thought to affect cAMP, appear to use ionic calcium (Ca2+) or metabolites of complex phosphoinositides (or both) as the intracellular second messenger signal. F. GROUP II.D Intracellular messenger for group II-D is a protein kinase–phosphatase cascade. Several have been identified, may use more than one kinase cascade. 10 References: Harper’s Illustrated Biochemistry Dr. Celina Vilches’ PPT