Synthesis and Degradation of Hormones

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)