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 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

Pregnenolone

2C

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 iodidation

OH CH2

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

CH

2

NH3+

OH

OH

CO2CH

CH

2

NH3+

OH

OHOH

CH

CH

2

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

Prostaglandines

COO- 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

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)