BIOCHEMISTRY

Hormones and related

biosignaling compoundspart 2

The major endocrine system and their target tissues

The adult cortex has 3 distinct layers [or zones].

The subcapsular area is called the zona glomerulosa and is associated

with the production of mineralocortocoids.

Next is zona fasciculata, which with the zona reticularis, produces

glucocorticoids and androgenes.

The glucocorticoids are 21-carbon steroids with many

actions, the most important of which is to promote

gluconeogenesis.

Cortisol is the predominant glucocorticoid in humans, and is made in

the zona fasciculata.

Corticosterone, made in the zonae fasciculata and glomerulosa, is less

abundant in humans.

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Steroid hormone

STEROIDS

MECHANISM OF

ACTION

H – hormon

R – receptor

HR – hormon-receptor

complex

STEROIDS nomenclature1

All steroid hormone have the

CYCLOPENTANOPERHYDROPHENANTRENE –

17-carbone structure with the 4 rings labeled A-D

Additional carbons (C18 and

C19) can be added at

positions 10 and 13 or as a

side chain attached to C17

(C20–C27).

STEROIDS nomenclature2

Steroid hormones and their precursors and methabolites

differ in number and location of double bonds, and

stereochemical configuration.

There are asymmetric

carbons (shaded)

STEROIDS nomenclature3

The nuclear substitutions in

the same plane as these

groups are designated ‘cis’or

‘β’ and represented in

drawings by solid lines.

Substitutions that project

behind the plane of the ring

system are designated ‘trans’

or ‘α’ and are presented asa

dashed line.

The angular methyl groups

(C18 and C19) at possition 10

and 13 project in front of the

ring system and serve as the

point of reference.

STEROIDS nomenclature4Double bonds are referred to by number of the preceding carbon.

Δ4 Δ5

Δ5

Cholesterol → 20α,22β-dihydroxycholesterol → Pregnenolonecytochrom P450 side chain cleavage enzyme

[activated by ACTH [adrenocorticotropic hormone] (or cAMP [cyclic adenozine mono phosphate])]

Synthesis and degradation

of 3’,5’-cyclic Adenosine

Monophosphat (cAMP) –secondary messenger for majority of

polypeptide hormones which activates

protein kinase A (A stands for cAMP) –

which catalyses phosphorilation of

proteins [transfer of phosphate group to

serin and threonine residues]

Adenylate cyclase – (mediated by

G-proteins)Phosphodiesterase (caffein and

theophylline [methylxanthine

derivatives] can inhibit

phosphodiesterasees and increase

the intracellular levels of cAMP)

R2C2-cAMP – dependent

protein kinase A

R2 – regulatory subunits C2

– catalytic subunits

C – active catalytic unit of

R2C2 – catalyses

phosphorylation of proteins

Action of cyclicAMP

The Mineralocorticoids are 21-carbon steroids.

The primary action, of these mineralocorticoid hormones is

to promote retention of Na+ and excretion of K+ and H+,

particularly in the kidney.

Aldosterone is the most potent hormone in this class, and it made

exclusively in zona glomerulosa.

Synthesis of aldosterone follows the mineralocorticoid

pathway and occurs in the zona glomerulosa.

Pregnenolone is converted to progesterone by the action of 2 smooth endoplasmatic

reticulum enzymes, 3β-hydroxysteroid dehydrogenase and Δ5,4 isomerase.

Progesterone is hydroxylated at the C21 position (by 21α-hydroxylase) to form 11-

deoxycorticosterone (chemical name: 21-hydroxy-4-pregnene-3,20-dione), which is an active (Na+-

retaining) mineralocorticoid. The next hydroxylation, at C11 (by 11β-hydroxylase),

produces corticosterone, which has glucocorticoid activity and is a weak

mineralocorticoid (it has less than 5% of the potency of aldosterone). In some species

(eg. rodents), it is the most potent glucocorticoid. C21 hydroxylation is necessary for

both mineralocorticoid and glucocorticoid activity, but most steroids with a C17

hydroxyl group have more glucocorticoid and less mineralocorticoid action. In the

zona glomerulosa, which does not have the smooth endoplasmatic reticulum enzyme

17α-hydroxylase, a mitochondrial 18-hydroxylase is present. The 18-hydroxylase acts

on corticosterone to form 18-hydroxycorticosterone, which is changed to aldosterone by

the conversion of the 18-alcohol to an aldehyde. This unique distribution of enzymes

and the special regulation of the zona glomeruloza have been led some investigators to

suggest that, in addition to the adrenal being 2 glands, the adrenal cortex is actually 2

separate organs.

1.pregnenolone → progesterone → deoxycoirticosterone →

corticosterone → aldosterone

3β-hydroxysteroid dehydrogenase + Δ5,4 isomerase

21α-hydroxylase

11β-hydroxylase

18-hydroxylasealdosterone synthase

Glucocorticoid synthesis.

Cortisol synthesis requires 3 hydroxylases that act sequentially on the C17, C21, and C11

positions. The first 2 reactions are rapid, while C11 hydroxylation is relatively slow. If

the C21 position is hydroxylated first, the action of 17α-hydroxylase is impeded and the

mineralocorticoid pathway is followed (forming corticosterone or aldosterone,

depending on the cell type). 17α-hydroxylase is a smooth endoplasmatic reticulum

enzyme that acts upon either progesterone or, more commonly, pregnenolone. 17α-

hydroxyprogesterone is hydroxylated at C21 to form 11-deoxycortisol, which is then

hydroxylated C11 to form cortisol, the most potent naturalglucocorticoid hormone in

humans. The 21-hydroxylase is a smooth endolasmatic reticulum enzyme, whereas the

11β-hydroxylase is a mitochondrial enzyme. Steroidogenesis thus involves the repeated

shutting of substrates into and out of the mitochondria of the fasciculata and reticularis

cells.

2.pregnenolone → 17α hydroxypregnenolone → 17α

hydroxyprpgesterone → 11-deoxycortisol → cortisol

3β-hydroxysteroid dehydrogenase

21α-hydroxylase

17α-hydroxylase

11β-hydroxylase

Androgen precursor Dehydroepiandrosterone and weak

androgen androstenedione are produced in zona fasticulata

and reticularis of the adrenal cortex.

These steroids are converted into more potent androgens in

extraadrenal tissues and become pathologic sources of androgens

when specific steroidogenic enzymes are deficient.

Estrogenes are not made in the normal adrenal in significant amounts,

but in certain cancers of the adrenal they may be produced, and

androgens of adrenal origin are important precursors of estrogen

(converted by peripherial aromatization) in postmenopausal women.

Androgen synthesis.

The major androgen or androgen precursors produced by the adrenal cortex is

dehydroepiandrosterone (DHEA). Most 17-hydroxypregnenolone follows the

glucocorticoid pathway, but a small fraction is subjected to oxidative fission and

removal of the 2-carbon side chain through the action of 17,20-lyase. This enzyme is

found in the adrenals and gonads and acts exclusively on 17α-hydroxy-containing

molecules. Adrenal androgen production increases markedly if glucocorticiod

biosynthesis is impressed by the lack of one of the hydroxylases. Most DHEA is

rapidly modified by the addition of sulfate, about half of which occurs in the adrenal

and the rest in the liver. DHEA sulfate is inactive, but removal of the sulfate results in

reactivation. DHEA is really a prohormone, since the actions of 3β-hydroxysteroid

dehydrogenase and Δ5,4 isomerase convert the weak androgen DHEA into the more

potent androstenedione. Small amounts of androstenedione are also formed in the

adrenal by the action of the lyase on 17α-hydroxyprogesterone. Reduction of

androstenedione at the C17 position results in the formation of testosterone, the most

potent adrenal androgen. Small amount of testosterone are produced in the adrenal by

this mechanism, but most of this conversion occurs in other tissues. Small amounts of

other steroids can be isolated from adrenal venous blood, including 11-

deoxycortisterone, progesterone, pregnelone, 17α-hydroxyprogesterone, and a very

small amount of estradiol (from the aromatization of testosterone). None of these

amounts are important in relation to production from other glands, however.

3.pregnenolone → 17α hydroxypregnenolone →

dehydroepiandrosterone → androstendiol → testosterone →

dehydrotestosterone

17α-hydroxylase

17,20-lyase

17β-hydroxysteroid dehydrogenase

3β-hydroxysteroid dehydrogenase

5α-reductase

4.pregnenolone → 17α hydroxypregnenolone →

dehydroepiandrosterone → androstenedione → estrone →

estriol

17α-hydroxylase

17,20-lyase

3β-hydroxysteroid dehydrogenase

aromatase

liver & placenta hydrogenase

5.pregnenolone → 17α hydroxypregnenolone →

dehydroepiandrosterone → testosterone → esradiol → estriol

17α-hydroxylase

17,20-lyase

17β-hydroxysteroid dehydrogenase 3β-hydroxysteroid dehydrogenase

aromatase

liver & placenta hydrogenase

Steroid

hormon

synthesis

PREDNISOLONE

DEXAMETHASONE

7 times more powerful than prednisolone

FLUTICASON

Representation of androgen biosynthesis on the testicular

microsomal membrane.

The membrane is shown as horizontal, in microsomal preparations, however,

it forms vesicles (A – androstenedione; T – testosterone)

Hormonal and

physiologic

changes

during a

typical human

menstrual

cycle.

Hormonal changes during a human menstrual cycle.

[LH – luteinizing hormone; FSH – follicle-stimulating hormone]

Hormone levels

during normal

pregnancy. (hCG

– human

chorionic

gonado-tropin,

hCS – human

chorionic

somato-mammo-

tropin)

Each cell of body receive constant input from membrane

proteins that act as information receptors

These membrane proteins sampling the surrounding

medium (controlled by homeostasis regulators) for pH,

osmotic strength, temperature, availability of energy sources

(compounds can be reduced) and oxygen (oxidative agents).

That all can be concern as receiving signals from outer

space for further action, its quality, amount, and force.

Cell action can be also concerned as a kind of biosignal

which is informing other cells about local states of tissue as

the signals can be concerned as local hormons

(paracrinic [neighbourhood cells], autocrinic [just on itself])

Model of a section of a phospholipid bilayer membrane

prostaglandines – are considered as locally acting hormones

– their related compounds are also known as eicosanoids

(εικοσι – twenty)

These compounds derivatives of hypotetical 20-carbon fatty

acid – prostanoic acid known as prostaglandines

hence, they are known also as prostanoids

Prostaglandines

Overview of

biosynthesis

of prosta-

glandins and

related

compounds

(5-HPETE – 5-

hydroxy-peroxy-

eicosa-tetra-enoic

acid;

PG –prosta-

glandins; PGI2 –

prosta-cyclin I2;

TXA2 –

thromboxane A2)

Prostaglandins classification

Prostaglandins

prostaglandines – as local hormones –

mediate the

-regulation of blood pressure (PGE, PGA, PGI2) are

vasodilator in function

-induce the symptoms of inflammation

-termination of pregnancy (PGE2, PGF2)

-paine and fever (along with histamine and bradykinin)

-regulation of gastric secretion (PGE)

-influence on immune system

-effects on respiratory function (PGE1, PGE2)

-influence on renal function (PGE – increase glomerulaf

filtration)

-effect on metabolism (through cAMP)

-platelete aggregation and trombosis (PGI2)

Leukotrienes – are synthesized by leucocites, mast cells, also

by sells of lung, heart, spleen due to lipoxygenase

(A4, B5, C4, D4, E4)

Slow-reacting substance of anaphylaxis – up to 1000 times

more potent than histamine or prostoglandins in its action as

stimulant of allergic reactions. Leucotriens are implicated in

asthma, inflammatory reactions, hypersensivity (allergy) and

heart attacks.

Leukotrienes cause contraction of smooth muscles

(bronchoconstriction, vasoconstriction, adhesion of white

blood cells and release of lysosomal enzymes).

Synthesis of

leucotrienes

Leucotrienes, Thromboxanes

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