Synthesis and Degradation of Hormones

1. Synthesis and Degradation of Hormones František Duška www.lf3.cuni.cz/ustavy/chemie.htm

2. Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates • thyroid hormones • catecholamines • Proteins and peptides • FA derivates - eikosanoids Receptor inside the cell Surface receptor

3. 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

4. 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

7. 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)

8. 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

9. 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

10. 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)

11. Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates • thyroid hormones • catecholamines • Proteins and peptides • FA derivates - eikosanoids Receptor inside the cell Surface receptor

12. Nitric oxide • NO: synthetized by NO-synthase

13. 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

14. Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates • thyroid hormones • catecholamines • Proteins and peptides • FA derivates - eikosanoids Receptor inside the cell Surface receptor

15. Thyroid hormones

16. T3 and T4 synthesis I- T3, T4 Folicular c.: -Tg synthesis -I-transport -Tg cleavage –deiodation of MIT& DIT ER štěpení Tg I- Thyreoglobuline In the coloid: -iodine oxidation -Tg iodidation I+ Iodidated Tg

17. Tg iodidation

18. Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates • thyroid hormones • catecholamines • Proteins and peptides • FA derivates - eikosanoids Receptor inside the cell Surface receptor

19. Catecholamine synthesis • Substrate = Phe or Tyr • Synthesis located in: adrenal medula, nerve tissue • Products: • dopamine, adrenaline (hormones) • noradrenaline (neurotransmiter)

20. Catecholamine synthesis

21. Catecholamine breakdown Inhibitors of MAO = antidepresive drugs

22. Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates • thyroid hormones • catecholamines • Proteins and peptides • FA derivates - eikosanoids Receptor inside the cell Surface receptor

23. 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

24. 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

25. Insulin synthesis

26. 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

27. Chemistry of Hormones • Steroids • Small molecules - NO • Amino acid derivates • thyroid hormones • catecholamines • Proteins and peptides • FA derivates - eikosanoids Receptor inside the cell Surface receptor

28. 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…

29. 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

30. Prostaglandines COX 1-3 Arachidonate PGG2 Cyclooxygenase inhibitors: - ASA (Aspirin) - paracetamole

31. Thromboxanes • Contain oxane ring • Synthetized from prostaglandines • Role in blood clotting

32. 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

33. 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)