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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 thyroid hormones catecholamines Proteins and peptides FA derivates - eikosanoids. Receptor inside the cell. - PowerPoint PPT Presentation
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Synthesis and Degradation of
Hormones
František Duškawww.lf3.cuni.cz/ustavy/chemie.htm
Chemistry of Hormones• Steroids • Small molecules - NO• Amino acid derivates
– thyroid hormones– catecholamines
• Proteins and peptides• FA derivates - eikosanoids Surface
receptor
Receptor inside the cell
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
OH OH
O
O
OCH2
OH
O
OH
CH2
O
O
OH CH2
O
O
OHOH
OH
CH2
O
O
OHOH CHO
-OOC
CH2
O
O
OHO
OH
123
4 678
11 12
1415
16
1718
19 21
26 27
PROGESTERONE
CORTISOLE
11
11
21
17
ALDOSTERONE
C21-OH
C21-OH
C11-OH, C17-OH
C11-OH, C18 ox.
19C
19C-steroids(testosterone)
1117
Cortisone
O
O
O
OH OH
OH
O
O
OH
O
OH
O
PROGESTERON(C21)
TESTOSTERON (C19)
ESTRADIOLE(C18)
Aromatase
2C
Androstendione
Pregnenolone2C
DHEA (dihydroepiandrosterone)
17 OH
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 androgensTreatment: 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
– thyroid hormones– catecholamines
• Proteins and peptides• FA derivates - eikosanoids Surface
receptor
Receptor inside the cell
Nitric oxide• NO: synthetized by NO-synthase
CH2
CH2
CH2
CH2
CH NH3+COO-
NH
NH2
O
CH2
CH2
CH2
CH2
CH NH3+COO-
NH
NH2
NH
CitrullineArginin
+ NADPH + H+ NADP+ + NO
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
– thyroid hormones– catecholamines
• Proteins and peptides• FA derivates - eikosanoids Surface
receptor
Receptor inside the cell
Thyroid hormonesI
OH O CH2
CH
NH2
COOH
I
I
I
OH O CH2
CH
NH2
COOH
I
I
I
Triiodthyronine (T3)
Thyroxine (T4)
T3 and T4 synthesis
ER
Thyreoglobuline
Iodidated Tg
štěpení Tg
T3, T4I-
I-
I+
Folicular c.: -Tg synthesis -I-transport -Tg cleavage –deiodation of MIT & DIT
In the coloid:-iodine oxidation -Tg iodidation
Tg iodidationOH C
H2
CHCO
NH
OH CH2
CHCO
NH
I
OH CH2
CHCO
NH
I
I
I
OH O CH2
CH
NH2
COOH
I
I
I
OH O CH2
CH
NH2
COOH
I
I
I
Thyreoglobuline
Thyreoglobuline
Tyr
MIT
Thyreoglobuline
DIT
Triiodthyronine (T3)
Thyroxine (T4)
Chemistry of Hormones• Steroids • Small molecules - NO• Amino acid derivates
– thyroid hormones– catecholamines
• Proteins and peptides• FA derivates - eikosanoids Surface
receptor
Receptor inside the cell
Catecholamine synthesis
• Substrate = Phe or Tyr• Synthesis located in: adrenal medula,
nerve tissue• Products:
– dopamine, adrenaline (hormones)– noradrenaline (neurotransmiter)
Catecholamine synthesis
CH2
CH
NH3+
COO- CH2
CH
NH3+
COO-OH CH2
CH
NH3+
OH
OH
COO-
CH2
CH2
NH3+
OH
OH
CO2CH
CH2
NH3+
OH
OHOH
CH
CH2
NH
OH
OHOH
CH3
Phenylalanin Tyrosin 3,4 DihydrOxyPhenylAlanin (DOPA)
+
Adrenalin Noradrenalin Dopamin
1. 2.
3.
4.5.
Catecholamine breakdown
CH
77COO-78
OH
CH3OOH
COMT
MAO
Inhibitors of MAO = antidepresive drugs
Chemistry of Hormones• Steroids • Small molecules - NO• Amino acid derivates
– thyroid hormones– catecholamines
• Proteins and peptides• FA derivates - eikosanoids Surface
receptor
Receptor inside the cell
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
– thyroid hormones– catecholamines
• Proteins and peptides• FA derivates - eikosanoids Surface
receptor
Receptor inside the cell
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
ProstaglandinesCOO- COO-
O
O
OOH
58
11 14
20
1
Kyselina arachidonová Prostaglandin G 2 Arachidonate PGG2
Cyclooxygenase inhibitors:- ASA (Aspirin)- paracetamole
COX 1-3
Thromboxanes• Contain oxane ring• Synthetized from prostaglandines• Role in blood clotting
COO-
O
O
OHThromboxane 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)