Biosynthesis of steroid hormones
Synthesis and hydroxylation of calciolsSynthesis and hydroxylation of calciols
Biochemistry II
Lecture 2 2008 (J.S.)
The major sites of steroid hormone biosynthesis
The adrenal cortex
- zona fascicularis and reticularis- zona fascicularis and reticularis
minor mineralocorticoids
glucocorticoids
adrenal androgensadrenal androgens
- zona glomerulosa
aldosteronealdosterone
The testes
- the Leydig cells testosterone- the Leydig cells testosterone
The ovaries
- the granulosa cells- the granulosa cells
and the developing follicle estrogens
- corpus luteum progesterone
The placenta progesterone (from maternal cholesterol)
estrogens (from both maternal and fetal
adrenal androgens)
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adrenal androgens)
CholesterolCholesterol
(cholest-5-ene-3β-ol) is the precursor for all steroid hormone synthesis.
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Cytochrome P450 monooxygenases
control the steroidogenesis:control the steroidogenesis:
The rate limiting step of the biosynthetic pathway that generates C21 steroids is
catalysed by P450scc (side-chain cleaving cholesterol 20,22-desmolase).catalysed by P450scc (side-chain cleaving cholesterol 20,22-desmolase).
(The dehydrogenation / isomerization is catalysed by 3β-hydroxysteroid dehydrogenase.)
Three sequential hydroxylations at C-21, C-17α, and C-11β are catalysed byThree sequential hydroxylations at C-21, C-17α, and C-11β are catalysed by
P450c21, P450c17, P450c11.
Unique is the hydroxylation / dehydrogenation at C-18catalysed by
P450 aldosterone synthase.P450 aldosterone synthase.
The splitting at C-17 that generates C19 steroids is catalysed by
P450c17 17-20 lyase / desmolase.
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P450c17 17-20 lyase / desmolase.
Steroid hormones are hydroxylated by the cytochrome P450 systemsSteroid hormones are hydroxylated by the cytochrome P450 systems
located partly in membranes of endoplasmic reticulum (P450c17, P450c21,
P450aro), partly in mitochondria (P450scc, P450c11β, P450AS).
These systems differs from the hydroxylating cyt P450 systems inThese systems differs from the hydroxylating cyt P450 systems in
membranes of endoplasmic reticulum in the liver – the reduction of
mitochondrial cyt P450 involves an additional component, the iron-sulphurmitochondrial cyt P450 involves an additional component, the iron-sulphur
protein adrenodoxin between the reductase and the cytochrome.
Steroid
O2
2H O
Steroid
2H2O
Hydroxylated
steroid
Electron transport to cyt P450
steroid
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Cholesterol is the precursor for other important steroids:
C
Cholesterol is the precursor for other important steroids:
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C24
C21
C19
C18
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Steroidogenesis
CHOLESTEROLCHOLESTEROL
Pregnenolone 17α-OH pregnenolone DHEA
(dehydroepiandrosterone)
Progesterone 17α-OH progesterone ANDROSTENDIONE
Gonades and peripheral tissues
DEOXYCORTICOSTERONE 11-Deoxycortisol TESTOSTERONE
Gonades and peripheral tissues
Corticosterone CORTISOL ESTRADIOLCorticosterone CORTISOL
18-OH corticosterone Cortisone
ESTRADIOL
Adrenal cortex
- zona glomerulosa
18-OH corticosterone
ALDOSTERONE
Cortisone
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ALDOSTERONE
Enzymes catalysing steroid synthesis:
17α-Hydroxylase / 17,20-lyaseChol. side chain cleavage enzyme
Cholesterol
3ββββ-Hydroxysteroid dehydrogenase
Pregnenolone DHEA
3ββββ-Hydroxysteroid dehydrogenase
PROGESTERONE Androstenedione
21-Hydroxylase
17-Oxosteroid reductase
TESTOSTERONE
DOC
11ββββ-Hydroxylase
TESTOSTERONE
Removal of C-19
DOC
Aldosterone synthase
Removal of C-19
Aromatization
of the ring A
ESTRADIOL
Corticosterone CORTISOL
Synthesis is enabled by small number
Aldosterone synthase
ESTRADIOL
ALDOSTERONE
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Synthesis is enabled by small number
of multifunctional enzymes.
ALDOSTERONE
CorticoidsCorticoids
are steroid hormones secreted from the adrenal cortex. The
principal types of adrenal steroid hormones are the glucocorticoidsprincipal types of adrenal steroid hormones are the glucocorticoids
and mineralocorticoids.
Glucocorticoids (such as cortisol)Glucocorticoids (such as cortisol)
• promote gluconeogenesis and the formation of glycogen,
• enhance the degradation of proteins and fat, and
• inhibit the inflammatory response.• inhibit the inflammatory response.
They enable animals to respond to stress.
Mineralocorticoids (primarily aldosterone)
• act on the kidney to increase the reabsorption of Na+ and the
excretion of K+, which leads to an increase in blood volume andexcretion of K+, which leads to an increase in blood volume and
blood pressure.
They are effective in keeping the water and mineral balance.They are effective in keeping the water and mineral balance.
Adrenal androgens - dehydroepiandrosterone and
androstenedione - are secreted from adrenal cortex, too.
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androstenedione - are secreted from adrenal cortex, too.
In adrenal cortex, there are three distinct cellular zones differing in the
enzymatic equipment. The three zones form two functional units that areenzymatic equipment. The three zones form two functional units that are
controlled independently.
The cells of the outer layer – zona glomerulosa – do not express
17α-hydroxylase so that they do not produce the precursors of glucocorticoids
and adrenal androgens. On the other hand, the gene for aldosterone synthase
is expressed only in that zone – the unique site of aldosterone production.is expressed only in that zone – the unique site of aldosterone production.
The synthesis and secretion of aldosterone is controlled by renin-angiotensin
systém; the influence of adrenocorticotropin (ACTH) is very weak and transient.
Both inner zones of adrenal cortex – zona fasciculata and reticularisBoth inner zones of adrenal cortex – zona fasciculata and reticularis
– produce glucocorticoids and androgens, the production of less effective
mineralocorticoids deoxycorticosterone (DOC) and corticosterone is not verymineralocorticoids deoxycorticosterone (DOC) and corticosterone is not very
important. The synthesis and secretion is controlled by ACTH.
Glucocorticoids
Adrenal androgensCatecholamines
Mineralocorticoids
Adrenal androgensCatecholamines
Medulla
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Medulla
Mineralocorticoids
Corticosterone
11β,21-Dihydroxypregn-4-ene-3,20-dione
is produced also in the zona fasciculata
and reticularis, but its biological effects
are much weaker than the effect of
Aldosterone
are much weaker than the effect of
aldosterone.
Aldosterone
is synthesized only in the zona glomerulosa of adrenal cortex.
10(hemiacetal form)
Synthesis of aldosterone in zona glomerulosaSynthesis of aldosterone in zona glomerulosa
Aldosterone
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Synthesis of aldosterone in zona glomerulosa of adrenal cortex
CHOLESTEROL
Chol. side chain cleavage enzyme ANGIOTENSIN II
Pregnenolone
3β-Hydroxysteroid dehydrogenase
ANGIOTENSIN I
Carboxypeptidase ACE
Progesterone
21-Hydroxylase
ANGIOTENSIN I
RENIN
DOC
11β-Hydroxylase
ANGIOTENSINOGEN
(plasma α -globulin)
RENIN
(proteinase)
Corticosterone
Aldosterone synthase
(plasma α2-globulin)
Secretion of the juxtaglomerular cells
is stimulated by
18-OH corticosterone
Aldosterone synthase
is stimulated by
- pressure decrease in arteriolae afferentes
- circulating catecholamines
- the decrease of [Na+] + [Cl-] in the tubular
ALDOSTERONE REABSORPTION of Na+, excretion of K+
- the decrease of [Na ] + [Cl ] in the tubular
liquid (detected by cells of macula densa)
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ALDOSTERONE REABSORPTION of Na+, excretion of K+
Glucocorticoids
Cortisol (hydrocortisone)
11β,17α,21-Trihydroxypregn-4-ene-3,20-dione
Glucocorticoids
11β,17α,21-Trihydroxypregn-4-ene-3,20-dione
Cortisol, the major glucocorticoid, is synthesized from progesterone by
hydroxylations at C-17, C-21, and C-11.
Cortisol secretion under basal (i.e., non-stressed) conditions ranges fromCortisol secretion under basal (i.e., non-stressed) conditions ranges from
22 µmol/d to 70 µmol/d (8 – 25 mg/d).
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Synthesis of steroids in zona fasciculata and zona reticularis:
CHOLESTEROL
Chol. side chain cleavage enzyme
Pregnenolone 17α-OH pregnenolone DHEA
Chol. side chain cleavage enzyme 17α-Hydroxylase / 17,20-lyase
Pregnenolone 17α-OH pregnenolone DHEA
Progesterone 17α-OH progesterone ANDROSTENDIONE
3β-Hydroxysteroid dehydrogenase
Progesterone 17α-OH progesterone ANDROSTENDIONE
21-Hydroxylase
DOC 11-Deoxycortisol
11β-Hydroxylase
Corticosterone CORTISOL
NEGATIVE FEEDBACK CONTROL
ACTH
(CORTICOTROFIN)
CORTICOLIBERIN
(CRF)
NEGATIVE FEEDBACK CONTROL
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(CORTICOTROFIN) (CRF)
Pregnenolone 17αααα-PregnenolonePregnenolone 17αααα-Pregnenolone
17αααα-Progesterone17αααα-Progesterone
11-Deoxycortisol11-Deoxycortisol
Cortisol
(Hydrocortisone)(Hydrocortisone)
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Adrenal androgens
The production of adrenal
androgens requires prior
17α-hydroxylation and17α-hydroxylation and
thus does not occur in the
zona glomerulosa.
Adrenal secretion of testosterone is minimal.Adrenal secretion of testosterone is minimal.
The adrenal androgens, dehydroepiandrosterone (DHEA),
DHEA sulfate, and androstenedione, have minimal
intrinsic androgenic activity, and they contribute tointrinsic androgenic activity, and they contribute to
androgenicity by their peripheral conversion to the more
potent androgens testosterone and
dihydrotestosterone.
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dihydrotestosterone.
Gonadal steroids
In male reproductive function, the three steroids of primary importance
are testosterone, dihydrotestosterone and estradiol.
In the female reproductive system, the mature ovary synthesizes and
secretes estrogens, progesterone, androgens, and their precursors.
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Testicular androgens
are responsible for the development of male secondary sex
characteristics. From a quantitative standpoint, the most importantcharacteristics. From a quantitative standpoint, the most important
androgen is testosterone secreted by the testicular Leydig cells.
Testosterone
17β-Hydroxyandrost-4-ene-3-one17β-Hydroxyandrost-4-ene-3-one
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In addition to testosterone, the testes secrete small amounts of the potent
androgen dihydrotestosterone, the weak androgens DHEA and
androstenedione, and estradiol, progesterone, etc.
About 80 % of the circulating concentrations of dihydrotestosterone andAbout 80 % of the circulating concentrations of dihydrotestosterone and
estradiol is derived by conversion of testosterone and its precursors
in peripheral tissues by the microsomal reductase.in peripheral tissues by the microsomal reductase.
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Steroid hormones of the ovary
C18
Estrogens
are required for the development of female secondary sexare required for the development of female secondary sex
characteristics and, along with progesterone, also participate in the
ovarian cyclus.
The ovary is normally the major source of estrogens, although theThe ovary is normally the major source of estrogens, although the
conversion of androgen precursors in other tissues is clinically
important after the menopause (and in some women with disorders ofimportant after the menopause (and in some women with disorders of
ovarian function).
The ovary is also the source of small amounts of testosterone and other androgens
that serve not only as precursors to estrogen synthesis but also are released into the
Estradiol
that serve not only as precursors to estrogen synthesis but also are released into the
circulation to act on peripheral tissues.
Estradiol
Estra-1,3,5(10)-triene-3,17β-diol
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Synthesis of estrogens in the ovary
Pregnenolone
Progesterone
Luteal phase
Synthesis of estrogens in the ovary
Progesterone
17α-Hydroxyprogesterone17α-Hydroxypregnenolone
DehydroepiandrosteroneFollicular phase
Estrogens are synthesized from
androgens by the enzymeandrogens by the enzyme
cytochrome P450 aromatase.
The process involves three steps:The process involves three steps:
– two successive hydroxylations of the methyl group at C-19 (the gem-diol then spontaneously loses
water to give aldehyde), and
– a third hydroxylation at C-2 which results in a product that rapidly and nonenzymatically loses formic
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– a third hydroxylation at C-2 which results in a product that rapidly and nonenzymatically loses formic
acid and forms an aromatic ring A.
Gestagens
CGestagens
Progesterone (pregn-4-ene3,20-dione)
prepares the lining of the uterus for implantation of an ovum and
C21
prepares the lining of the uterus for implantation of an ovum and
is also essential for the maintenance of pregnancy.
The ovary produces and secretes large amounts of progesterone
during the luteal phase of the cycle.during the luteal phase of the cycle.
However, it also serves as a minor precursor for androgens and estrogens.
Cholesterol Pregnenolone
Androgens
Progesterone
Estrogens
Progesterone is rapidly cleared from the circulation converted (by reduction)
to pregnanediol and conjugated to glucuronate in the liver.
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Synthesis and hydroxylation of calciolsSynthesis and hydroxylation of calciols
The calciols (formerly calciferols, several forms of vitamin D) are a family of
sterols that affect calcium homeostasis.sterols that affect calcium homeostasis.
The daily requirement for calciols is 5 - 20 µg (200 – 800 IU).
The D-provitamins, ergosterol and 7-dehydrocholesterol, are widely distributed in theThe D-provitamins, ergosterol and 7-dehydrocholesterol, are widely distributed in the
animals and plants.
Most natural foods have a low content of vitamin D3. It is present in egg yolk, butter,
cow's milk, beef and pork liver, animal fat and pork skin.
The most important vitamin D (D2) source is fish oil, primarily liver oil.
≡≡
The calciols are 9,10-sekosteroids, in which the ring B is opened.
Calciol (cholecalciferol, vitamin D3) Ercalciol (ergocalciferol, vitamin D2)
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The calciols are 9,10-sekosteroids, in which the ring B is opened.
Calciol (vit. D3) is synthesized from 7-dehydrocholesterol by photolysis that is
a cause of opening of the ring B:a cause of opening of the ring B:
Cholesterol THE LIVER CELLS
7,8-Dehydrogenation7,8-Dehydrogenation
Lumisterol
TachysterolTachysterol
7-Dehydrocholesterol
Capillaries of the SKIN
A high-speed photolysis
An intermediate
(praevitamin)
A high-speed photolysis
λmax = 295 nm
Slow thermal conversion
(praevitamin)
Calciol (vit. D3)Calciol is slowly released into blood
and bound to serum DBP (D vit. binding protein).
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and bound to serum DBP (D vit. binding protein).
Calciol is an inactive precursor of calcitriol, the most potent biologically
active form of vitamin D.active form of vitamin D.
The hydroxylation of calciols
C-25
The LIVER CELLS The RENAL TUBULAR CELLS 1α
The LIVER CELLS
25-Hydroxylation
(monooxygenase, cyt P450)
The RENAL TUBULAR CELLS
1α-Hydroxylation
(monooxygenase, cyt P450)
Calciol Calcidiol Calcitriol
Calcidiol is the major circulating metabolite of calciol. Its biological half-life is rather long, approx.
Calciol
(Cholecalciferol)
Calcidiol
(25-Hydroxycholecalciferol)
Calcitriol
(1α,25-Dihydroxycholecalciferol)
A CALCIOTROPIC STEROID HORMONE
Calcidiol is the major circulating metabolite of calciol. Its biological half-life is rather long, approx.
20 - 30 days. The concentration of calcidiol in blood plasma informs of the body calciol saturation.
Seasonal variations are observed.
25-Hydroxylation of calcidiol is inhibited by the high concentrations of calcidiol and calcitriol25-Hydroxylation of calcidiol is inhibited by the high concentrations of calcidiol and calcitriol
(feedback control), calcitonin, and the high intake of calcium in the diet.
Calcitriol has a short biological half-life. 1α-Hydroxylation is stimulated by parathyrin (PTH), inhibited
by calcitonin and high concentrations of calcitriol.
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by calcitonin and high concentrations of calcitriol.
Biological action of calcitriol (1,25-(OH)2D3)
In the intestine – increased absorption of Ca2+ by enterocytes:
- Induction of a change in conformation of the calmodulin in cytosol – transfer of Ca2+- Induction of a change in conformation of the calmodulin in cytosol – transfer of Ca2+
across the cytoplasmatic membrane is supported;
- Induction of the calbindin synthesis in cytosol (CaBP, calcium-binding protein), CaBP
enables the transport of Ca2+ within the cell;
- Induction of the Ca2+-ATPase synthesis, that enables the export of Ca2+ into the
extracellular fluid.extracellular fluid.
In the bone – it regulates both the resorption and regeneration of bone tissue
- Induction of the osteocalcin synthesis (bone Gla protein, BGlaP), but the control
mechanismus is not yet fully explained.
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