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Synthesis and Degradation of Hormones František Duška www.lf3.cuni.cz/ustavy/chemie.htm Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates Receptor inside the cell – thyroid hormones – catecholamines • Proteins and peptides • FA derivates - eikosanoids Surface receptor The story of Libor • 5-yr. old boy. After a common cold several days ago has been vomiting, looses weight. No fever of diarhea, mother reffers him to be „disappearing in front of eyes“ • History: Birth weight 2800 g, parotitis at age 3, otherwise always healthy. • Physical examination: 110 cm, 14,6 kg, PB 80/40, P 130/min, signs of dehydration, hyperpigmentation of axillary and genital regions, presence of discreet pubic hair The story of Libor • Lab: Na 113 mM, K 5,8 mM, Cl 86, metabolic acidodosis • plasma 17-OH progesterone : 12,45 ug/dl (normal: <1 ug/dl) • Plasma cortisole 38 uM at baseline (ref.r.: above 200) and after stimulation with i.v. ACTH: 59 uM (ref.r. above 550) • Dg: Congenital adrenal hyperplasia – defect of 21-steroidhydroxylase 21 19 12 17 11 -OOC 18 1 14 2 8 15 16 3 HO 4 6 7 26 27 O HO C21-OH 19C-steroids (testosterone) 21 H2C OH O 19C O O PROGESTERONE HO C21-OH H2C OH O C11-OH, C17-OH HO 11 O O H2C OH 17 O OH CORTISOLE C11-OH, C18 ox. HO 11 O H2C OH CHO O ALDOSTERONE O 11 O H2C OH 17 O OH Cortisone O O PROGESTERON HO (C21) O Pregnenolone 2C 2C O O O Androstendione HO DHEA (dihydroepiandrosterone) 17 OH OH OH Aromatase O TESTOSTERON (C19) HO ESTRADIOLE (C18) Steroid hormone synthesis • C21: – progesterone: directly from pregnenolone – cortisol: from progesterone, hydroxylation at 11,17 and 21 – aldosterone: from progesterone, 11 and 21 hydroxylation, 18 oxidation to aldehyde • C19: form progesterone or pregnenolone: during 2c shortage at C17 oxogroup, and susequently OH testosterone • C18: estrogen: aromatase (cleaves C18) Regulation of steroid synthesis • 3 regulatory steps: – cholesterol release from internalized LDL – StAR protein = cholesterol transport through inner mitochondrial membrane – SCC = mitochondrial side chain cleavage enzyme • Signal: pituitary hormones(ACTH, LH, FSH) or angiotensine The story of Libor • Defect of 21 OH-H = block of cortisol and aldosterone synthesis, pathway redirected to androgens (testosterone and others) • Vomiting, weakness: cortisol insufficiency, disturbed internal environment by aldosterone • Hyperpigmentation: increased ACTH • Pubertas praecox: due to androgens Treatment: substitution of hormones behind the enzymatic block Steroid hormone breakdown • Steran core cannot be cleaved • In the liver: hydroxylation and conjugation with glucuronides or sulphates • Urinary excretion: – of metabolites – of unchanged hormones (UFC) Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates Receptor inside the cell – thyroid hormones – catecholamines • Proteins and peptides • FA derivates - eikosanoids Surface receptor Nitric oxide • NO: synthetized by NO-synthase NH2 NH NH CH2 CH2 + NADPH + H+ CH2 CH2 HC NH3+ COOArginin NH2 O NH CH2 NADP+ + NO CH2 CH2 CH2 HC NH3+ COOCitrulline Nitric oxide • NO-synthase (NOS) – in neurons: NOS-I: neurotransmission – in makrophAGES: NOS-II: kills bacteria – endothelial: NOS-III: difusion of NO toward smooth muscle, aktivation of sGC cGMP vasodilation • Clinical correlation: – nitrates in the treatment of angina – refractory hypotension during septic shoc Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates Receptor inside the cell – thyroid hormones – catecholamines • Proteins and peptides • FA derivates - eikosanoids Surface receptor Thyroid hormones I HO I O I Triiodthyronine (T3) I HO I O I H C C COOH H2 NH2 I Thyroxine (T4) H C C COOH H2 NH2 T3 and T4 synthesis IFolicular c.: Tg synthesis -I-transport -Tg cleavage –deiodation of MIT & DIT T3, T4 ER štěpení Tg Thyreoglobuline I- I+ Iodidated Tg In the coloid: -iodine oxidation -Tg iodidation Tg iodidation Thyreoglobuline CO C CH HO H2 NH HO I HO H C C COOH H2 NH2 O I Triiodthyronine (T3) Tyr I I Thyreoglobuline CO C CH HO H2 NH MIT I I O I I Thyroxine (T4) I HO I DIT Thyreoglobuline CO C CH H2 NH H C C COOH H2 NH2 Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates Receptor inside the cell – thyroid hormones – catecholamines • Proteins and peptides • FA derivates - eikosanoids Surface receptor Catecholamine synthesis • Substrate = Phe or Tyr • Synthesis located in: adrenal medula, nerve tissue • Products: – dopamine, adrenaline (hormones) – noradrenaline (neurotransmiter) Catecholamine synthesis C H2 1. H C H C C COOH2 NH 3+ HO COO- NH 3+ Phenylalanin Tyrosin 2. H C C COOH2 NH 3+ HO HO 3,4 DihydrOxyPhenylAlanin (DOPA) 3. H C HO H2 C 5. H C HO OH NH HO Adrenalin CH 3 HO Noradrenalin H2 C OH NH 3+ 4. C H2 HO HO Dopamin H2 C + NH 3+ CO2 Catecholamine breakdown MAO HO H C COO- 77 78 OH CH3O COMT Inhibitors of MAO = antidepresive drugs Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates Receptor inside the cell – thyroid hormones – catecholamines • Proteins and peptides • FA derivates - eikosanoids Surface receptor Protein and peptide hormones • CNS mediators: neuropeptides, opioids • Hypothalamic releasing hormones and pituitary peptides • Insulin and glucagone • Growth factors: IGF, CSF, EPO • Intestinal hormones …and many others General steps of peptide synthesis • • • • Expression of “pre-pro” protein Transport to ER Splitting the signaling sequence Cleavage to definite peptide(s) and final modification in Golghi – proinsulin to insulin – proopiomelanocortine to MSH and ACTH Insulin synthesis Degradation of peptide hormones • Lyzosomal after endocytosis of complex hormone-receptor • Chemical modification (liver): rearrangement of S-S bridges, cleavage • Renal excretion of small peptides Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates Receptor inside the cell – thyroid hormones – catecholamines • Proteins and peptides • FA derivates - eikosanoids Surface receptor Eikosanoids • Derivates of arachidonic acid (20C:5,8,11,14). • Paracrine action, low plasma concentration, short halflife, no storage • Many of functions: – immunity/inflamation – blood clotting – microcirculation… Eikosanoids • General steps of synthesis: – release of arachidonic acid from membrane PL (PLA2, after cleavage of PIP2 by PLC) – cyclooxygenase (COX) synthetizes prostaglandines and thromboxanes – lipooxygenase synthetizes leucotriens Prostaglandines 5 8 1 COO20 11 COX 1-3 O COO- O 14 Kyselina arachidonová Arachidonate Cyclooxygenase inhibitors: - ASA (Aspirin) - paracetamole OOH Prostaglandin G2 PGG2 Thromboxanes • Contain oxane ring • Synthetized from prostaglandines • Role in blood clotting COO- O O OH Thromboxane A2 Leucotriens • Lipoxygenase: adds hydroperoxy (OOH) group to C2, 12 or 15 of arachidonic acid • HPETE: hydroperoxyeikosatetrenoic acid • Conjugation with Cys or GSH • Clinical correlations: antileucitriens in the treatment of bronchial asthma Conclusion • Knowledge of hormonal syntetic pathways makes us – to understand basis of disease (CAH, endocrinologic hypofunction syndromes) – to be able to interpret lab values (plasma C-peptide, UFC, urine vanilmandelic acid) – to understand mechanisms of action of common drugs (like Aspirine or antidepressants)