Hormones & related bio signaling compounds (Part 2)

1. BIOCHEMISTRY
Hormones and related
biosignaling compounds
part 2

2. The major endocrine system and their target tissues

3. 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.

4. 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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6. Steroid hormone

7. STEROIDS
MECHANISM OF
ACTION
H – hormon
R – receptor
HR – hormon-receptor
complex

8. STEROIDS nomenclature1
All steroid hormone have the
CYCLOPENTANOPERHYDROPHENANTRENE –
17-carbone structure with the 4 rings labeledA-D
Additional carbons (C18 and
C19) can be added at
positions 10 and 13 or as a
side chain attached to C17
(C20–C27).

9. 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)

10. 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.

11. STEROIDS nomenclature4
Double bonds are referred to by number of the preceding carbon.
Δ4 Δ5
Δ5

12. Cholesterol → 20α,22β-dihydroxycholesterol → Pregnenolone
cytochrom P450 side chain cleavage enzyme
[activated by ACTH [adrenocorticotropic hormone] (or cAMP [cyclic adenozine mono phosphate])]

13. 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)

14. 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

15. 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.

16. Synthesis of aldosterone follows the mineralocorticoid
pathway and occurs in the zona glomerulosa.
Pregnenolone is converted to progesterone by the action of 2 smoothendoplasmatic
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 reticulumenzyme
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.

17. 1.pregnenolone → progesterone → deoxycoirticosterone →
corticosterone → aldosterone
3β-hydroxysteroid dehydrogenase + Δ5,4 isomerase
21α-hydroxylase
11β-hydroxylase
18-hydroxylase
aldosterone synthase

18. 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 andthe
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.

19. 2.pregnenolone → 17α hydroxypregnenolone → 17α
hydroxyprpgesterone → 11-deoxycortisol → cortisol
3β-hydroxysteroid dehydrogenase
21α-hydroxylase
17α-hydroxylase
11β-hydroxylase

20. 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.

21. 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. DHEAsulfate 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.

22. 3.pregnenolone → 17α hydroxypregnenolone →
dehydroepiandrosterone → androstendiol → testosterone →
dehydrotestosterone
17α-hydroxylase
17,20-lyase
17β-hydroxysteroid dehydrogenase
3β-hydroxysteroid dehydrogenase
5α-reductase

23. 4.pregnenolone → 17α hydroxypregnenolone →
dehydroepiandrosterone → androstenedione → estrone →
estriol
17α-hydroxylase
17,20-lyase
3β-hydroxysteroid dehydrogenase
aromatase
liver & placenta hydrogenase

24. 5.pregnenolone → 17α hydroxypregnenolone →
dehydroepiandrosterone → testosterone → esradiol → estriol
17α-hydroxylase
17,20-lyase
17β-hydroxysteroid dehydrogenase 3β-hydroxysteroid dehydrogenase
aromatase
liver & placenta hydrogenase

25. Steroid
hormon
synthesis

26. PREDNISOLONE

27. DEXAMETHASONE
7 times more powerful than prednisolone

28. FLUTICASON

29. 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)

30. Hormonal and
physiologic
changes
during a
typical human
menstrual
cycle.

31. Hormonal changes during a human menstrual cycle.
[LH – luteinizing hormone; FSH – follicle-stimulating hormone]

32. Hormone levels
during normal
pregnancy. (hCG
– human
chorionic
gonado-tropin,
hCS – human
chorionic
somato-mammo-
tropin)

33. 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])

34. Model of a section of a phospholipid bilayer membrane

35. 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

36. Prostaglandines

37. 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 –
thromboxaneA2)

38. Prostaglandins classification

39. Prostaglandins

40. 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)

41. 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).

42. Synthesis of
leucotrienes

43. Leucotrienes, Thromboxanes

44. Thank YOU for ATTENTION