Download ppt

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)