Hormones: Classification. Hormones: Classification. Peptide Hormone Synthesis, Packaging, and Release

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1 Hormones: Classification Hormones: Classification Be able to give types and example. Compare synthesis, half-life and location of receptor 1. Peptide or protein hormones Insulin from amino acids 2. Steroid hormones Sex steroids; estrogen, lipophilic 3. Amine hormones epinephrine Table 7-1 Peptide Hormone Synthesis, Packaging, and Release 1 Messenger RNA on the ribosomes binds amino acids into a peptide chain called a preprohormone The chain is directed into the ER lumen by a signal sequence of amino acids. Endoplasmic reticulum (ER) Ribosome 2 Enzymes in the 3 The prohormone 4 Secretory vesicles containing 5 The secretory 6 ER chop off the passes from the enzymes and prohormone vesicle releases signal sequence, ER through the bud off the Golgi. The enzymes its contents by creating an Golgi complex. chop the prohormone into one exocytosis into inactive or more active peptides plus the extracellular prohormone. additional peptide fragments. space. Golgi complex Active hormone The hormone moves into the circulation for transport to its target. To target Peptide Hormone Synthesis, Packaging, and Release (a) Signal processes to + + Preprohormone Hormone Other peptides sequence TRH + + PreproTRH (242 amino acids) 6 TRH (3 amino acids each) (b) Transport vesicle 3 Peptide fragment Prohormone processes to Active hormone(s) + Other peptide fragments Prohormone 4 Secretory vesicle Release signal 5 6 (c) Pro-opiomelanocortin + ACTH lipotropin endorphin Fragment 2 Capillary endothelium Proinsulin Insulin C-peptide 1 mrna Signal sequence Preprohormone Cytoplasm ECF Plasma Figure 7-3 Figure 7-4 Peptide Hormone-Receptor Complex Surface receptor Hormone binds Enzyme activation Open channels Second messenger systems Cellular response Peptide Hormone-Receptor Membrane receptors Complex and signal transduction for peptide hormones KEY Opens ion channel TK = Tyrosine kinase AE = Amplifier enzyme G = G protein Second messenger system phosphorylate Proteins Cellular response Figure 7-5 1

2 Steroid Hormones: Features Steroid Hormones: Structure Cholesterol is the parent compound for all steroid hormones. Cholesterol-derived Lipophilic and can enter target cell Cytoplasmic or nuclear receptors (mostly) Activate DNA for protein synthesis Slower acting, longer half-life Examples Cortisol, estrogen, and testosterone Adrenal cortex Aldosterone modified by enzymes to make steroid hormones such as In adrenal cortex In ovary Ovary Cortisol Estradiol (an estrogen) Figure 7-6 Steroid Hormones: Action Blood Steroid Cell surface receptor 1 Most hydrophobic steroids are bound to vessel hormone plasma protein carriers. Only unbound hormones can diffuse into the target cell. 2a Rapid responses 1 2 Steroid hormone receptors are in the cytoplasm or nucleus. Protein 2 carrier Nucleus Cytoplasmic 2a Some steroid hormones also bind to Nuclear receptor membrane receptors that use second receptor messenger systems to create rapid cellular responses. DNA Interstitial 3 The receptor-hormone complex binds to fluid DNA and activates or represses one or 3 more genes. Endoplasmic reticulum Cell Transcription 4 Activated genes create new mrna that membrane produces mrna 5 moves back to the cytoplasm. 4 New Translation proteins 5 Translation produces new proteins for cell processes. Amine Hormones: Features Derived from one of two amino acids Tryptophan Tyrosine Ring structure Figure 7-7 Amine Hormones: Examples Tyrosine Amine Hormones: Structure Thyroid hormones Catecholamines Epinephrine Norepinephrine Dopamine Catecholamines Dopamine Thyroid hormones Thyroxine (Tetraiodothyronine, T 4) Norepinephrine Epinephrine Triiodothyronine (T 3) Figure 7-8 2

3 Endocrine Reflex Pathways Stimulus Afferent signal Integration Efferent signal (the hormone) Physiological action Negative feedback Negative feedback KEY Blood Endocrine Eat Reflex a meal glucose Pathways: Stimulus Receptor Stretch receptor Insulin digestive tract release Efferent path Effector Tissue response Afferent neuron Sensory neuron CNS Efferent neuron Integrating center Efferent neuron Systemic response Pancreas Insulin Blood glucose Glucose uptake and utilization Target tissues Figure 7-9 Genes and enzymes: hormone synthesis Synthesis of protein and peptide hormones by gene transcription Post transcriptional and post translational modifications, packaging of hormones Hormone diversity Synthesis of steroid hormones from small molecular weight presursors Steroidogenic enzymes Transport and peripheral conversion of steroid hormones Hormone synthesis Peptides and proteins Water soluble, made from large precursor molecules - prohormones. Steroids and iodinated tyrosines Lipid soluble, made from low molecular weight precursors Morphology: Peptides - secretory granules, RER. Steroids - lipid droplets Protein/peptide secreting cell Steroid secreting cells Hormone synthesis 3

4 Synthesis of protein and peptide hormones Gene transcription (controlled by transcription factors) Processing of the initial mrna transcript to mature mrna excision of introns and modifications of the 3 and 5 ends Translation of mrna Bound to the polyribosomes of RER, the mrna acts as a template for assembling amino acids by way of trna Post translation processing Cleavage of large prohormone; can also include folding of polypeptide chain and addition of carbohydrates (glycosylation) Transcription Post-transcriptional modifications - removal of introns, 5 & 3 modifications Translation of mature RNA Post-translational processing - cleavage of pro-hormone, folding of protein molecule, glycosylation Packaging of hormones Signal sequence docking protein on RER As amino acids are assembled they are internalized into the RER RER Golgi apparatus Formation of secretory granules storage Secretion by exocytosis Packaging of hormones Signal sequence finds docking protein on RER As amino acids are assembled they are internalized into the RER RER Golgi apparatus Formation of secretory granules storage Secretion by exocytosis Membrane traffic in hormone-secreting cells Synthesis active hormone signal hormone redundant sequence Signal sequence + prohormone = pre-prohormone Active hormone + redundant sequence prohormone 4

5 Diversification of protein and peptide hormones Synthesis of insulin Homologous hormones Gene duplication - homologous families of hormones Processing of mrna: One gene two hormones Post translational processing One prohormone several hormones Homologue hormone Growth Hormone Prolactin Ancestral gene Growth hormone Prolactin Human placental lactogen Also oxytocin and vasopressin Homologous families of hormones Homologous glycoprotein hormones LH(hCG) FSH TSH and sub-units. unit common, unit biological activity Ancestral gene gonadotrophin TSH LH (hcg) FSH 5

6 One gene, two hormones - post transcriptional modifications One gene several hormones - post translational modifications Steroid synthesis Steroid hormone synthesis Cholesterol bound to sterol transfer protein - transported to mitochondria StAR protein transports cholesterol to inner mitochondrial membrane Cholesterol to pregnenolone by side chain cleavage enzyme, P450scc Between mitochondria and SER steroids synthesised by hydroxylase enzymes STEROID SYNTHESIS SIMPLIFIED Cholesterol Pregnenolone Progesterone 17 OH Progesterone Outline of steroid synthesis in the adrenal cortex and gonads Aldosterone Cortisol Androgens Steroids highly conserved Oestrogens 6

7 Steroid synthesis in the adrenal cortex Pregnenolone 3 -HSD Progesterone Conversion of androgens to oestrogens by aromatase Genes coding for the P450 enzymes are abbreviated to CYP 17 -hydroxyprogesterone Aromatase Androstenedione 17 hydroxylase 17 -HSD type 5 Testosterone Most steps in steroid synthesis require 17 -HSD type 1 cytochrome P450 hemecontaining enzymes Oestrone (E1) Oestradiol (E2) Aromatase Synthesis of thyroid hormones Active uptake of iodine into follicular cell Oxidation of iodide to iodine Iodination of tyrosine residues of thyroglobulin and apical-colloid interface Storage in colloid Uptake of thyroglobulin droplets into follicle cell Release and secretion of T3 and T4 Active uptake of iodine Oxidation of iodide to iodine Iodination of tyrosine residues at apical/colloid interface to form MIT and DIT Uptake of thyroglobulin into the lumen of the follicle Peripheral conversion of thyroid and steroid hormones T 4 T 3 Testosterone dihydrotestosterone Testosterone oestradiol Vitamin D (synthesised in skin) dihydroxy vitamin D. Transport of steroid and thyroid hormones An equilbrium exists between bound and free hormone. H + BG H.BG K eq = [H.BG] (H bound) [H] [BG] (H free) [H] = [H.BG] x 1 K eq [BG] e.g. transcortin, sex hormone binding globulin, transthyretin 7

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