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8/7/2019 Biosynthesis of steroid hormones
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BIOSYNTHESIS OF STEROIDHORMONES
DR. SUMREENA MANSOOR
ASSISTANT PROF OF BIOCHEMISTRY
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` Chemical nature of the adrenal
hormones
` Outline the steps involved in steroid
biosynthesis in adrenal cortex` Transport of adrenocortical steroids
` Adrenocortical hormone metabolism
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3
INTRODUCTION
Introduction
Structure, Nomenclature, Synthesis
Adrenocorticoids
Glucocorticoids, Mineralocorticoids
Male Sex Hormones
Androgens Female Sex Hormones
Estrogens and Progestins
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Composed of 3 layers (zones)
` Outer zone (zona glomerulosa)
produces aldosterone
(mineralocorticoid)` Middle zone (zona fasciculata)
produces cortisol (glucocorticoids)
` Inner zone (zona reticularis)
produces androgens (precursorsDHEA, Androstenedione)
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A SPECIAL NOMENCLATURE DESCRIBES THE
CHEMISTRY OF STEROIDS
COMMON C-17 COMPOUND(CYCLOPENTANOPERHYDROPHENANTHREIN
RING)
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4/6/2011MEDC 603 Steroids 9
STRUCTURES OF STEROIDS
CH
3
CH
3
A B
C D1
2
3
45
6
7
8910
1112
13
1415
16
1719
18
Structure and Nomenclature of the Steroid Nucleus
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4/6/2011MEDC 603 Steroids 10
STRUCTURES OF STEROIDSStructure and Nomenclature of the Steroid Side-chain
CH3
CH3
CH3
CH3
CH3
20
21
22
23
24 25
26
27
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Additional carbons can be added atC-10, C-13 and side chain on C-17
o Number and location of double
bonds
o Methyl groups at C-10 and C-13
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Glucocorticoids (Cortisol C-21)
Mineralocorticoids (aldosterone C-21)
Androgens (DHEA C-19) ALL THESE HORMONES ACT VIA GENE
EXPRESSION AND REGULATE
GLUCONEOGENESIS , Na+
, K+
and H+
BALANCE
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Glucocorticoids essential for adaptationto stress. Synthetic analogs are used as
potent anti-inflammatory agents
Excessive or deficient plasma levels of
these glucocorticoids, mineralocorticoids
and androgens result into disease or
serious life threatening complications
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4/6/2011MEDC 603 Steroids 16
CHOLESTEROL
C3
C3
C3
C3
C3
O
cholesterol
liver various tissues
Bile Acids(cholic acid, desoxy
cholic acid, etc.)
ormones(testosterone, progesterone
cortisol, estradiol, etc.)
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GLUCOCORTICOID BIOSYNTHESIS
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SEVERAL ENZYMES ARE INVOLVED INTHE BIOSYNTHESIS OF ADRENAL
STEROID HORMONES Plasma cholesterol is the main precursor
ACTH stimulated esterase release freecholesterol
CHOLESTEROL TRANSPORTED TO INNER MITOCHONDRIAL MEMBRANE BY (STAR:STEROIDOGENIC ACUTE REGULATORYPROTEIN) AND UNDERGOES SEQUENTIAL
HYDROXYLATIONS AT C-22 AND C-20 BYCYTOCHROME P-450 SIDE CHAIN CLEAVAGEenzymes(p-450scc)form PREGNANOLONE
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ADRENAL STEROID HORMONES
All mammalian steroids are formed from
pregnanolone, in mitochondria and (SER) by
following enzymes
Hydroxylases and NADPH Dehydrogenases zona glomerulosa
Isomerase
Lyase
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(Zona fasciculata), (cortisol C-21)
Only requires three hydroxylasesfor sequential addition of OH group
on C-17, C-21 and C-11 positions
First two reactions are rapid
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CholesterolMit. Scc enzyme
Pregnenolone
Cytoplasmic 3 -Of DH 4,5
ISOMERASEProgesterone
In Zona fasiculata Cytoplasmic 17 ±HYDROXYLAS
(SER)
Cytoplasmic 21 ±HYDROXYLA
(SER)
11 - HYDROXYLASE
MITOCHONDRIA
Cortisol
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CholesterolMit. Scc enzyme
Pregnenolone
Cytoplasmic 3 -Of DH
4,5
ISOMERASEProgesterone
In Zona glomerulosa Cytoplasmic 21 ±HYDROXYLASE
MITOCHONDRIAL 11 - HYDROXYLASE
MITOCHONDRIAL 18- HYDROXYLASE
Aldosterone
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activated to turn
on pathways
Cholesterol Pregnenolone Progesterone
11-Deoxy-
cortisone21-hydroxylase
Progesterone Aldosterone
General pathways for the synthesis of aldosterone and cortisol in the adrenalcortex
11-Deoxy-
cortisolProgesterone Cortisol
21-hydroxylase
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CholesterolMit. Scc enzyme
Pregnenolone
Cytoplasmic 17 ±HYDROXYLASE17 -Hydroxypregnenolone
In Zona reticularis Cytoplasmic 2C
Side chain cleavage
Dehydroepiandrosterone
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DHEA acts as prohormone
converted to testosterone (the most
Potent androgen)
ANDROGEN SYNTHESIS
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Pathway for formation of androgens in the adrenal cortex.
Pregnenolone D EA AndrostenedionAndrostenedione
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Estrone
(produced in both male andfemale adipose cells)
Pathways for the synthesis of testosterone (testes) andthe estrogens estradiol (ovaries) and estrone (adiposecells)
Cholesterol Pregnenolone Progesterone
Progesterone Androstenedione Testosterone(pathway ends
here in testes)
Estradiol
(pathway continues to
here in ovaries)
In obese men, overproduction of estrogen in fat cellscan cause gynecomastia = excessive male breastdevelopment
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To form cortisol, the adrenalgland requires cholesterol, whichis then converted biochemically
into steroid hormones.Interruptions in the delivery of cholesterol include Smith-Lemli-
Opitz syndrome andabetalipoproteinemia.
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` Congenital adrenal hyperplasia
Most common in various forms:
` 3-hydroxysteroid dehydrogenase
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3-hydroxysteroid dehydrogenase
No Glucocorticoids, Mineralocorticoids,
Active androgen and estrogenSalt excretion in urine
Female like genitalia
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17-hydroxylase No sex hormone and Cortisol
Mineralocorticoids-----Hypertension
Female like genitalia
21-hydroxylase Mineralocorticoids, glucocorticoids and
Corticosterone absent
Excessive Androgen masculinization of
external genitalia
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11-hydroxylase
Mineralocorticoids and glucocorticoidsabsent
Deoxycorticosterone causes fluidretention
Excessive Androgen masculinization of external genitalia
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` Autoimmune destruction of theadrenal cortex is cause by animmune reaction against the
enzyme 21-hydroxylase
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` Some medications interferewith steroid synthesis
enzymes (e.g. ketoconazole),while others accelerate thenormal breakdown of hormones by the liver (e.g.rifampicin, phenytoin)
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.` In adrenal Cushing's, excess Cortisol
is produced by adrenal gland tumors,hyperplastic adrenal glands, or
adrenal glands with nodular adrenalhyperplasia.
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A. Secretion of steroidhormones
Little storage and releasedinto plasma when made Cortisol release by ACTH
release
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B. Plasma transporta. Glucocorticoids (Cortisol)(i) Bound form with corticosteroid
binding globulin (CBG) orcalled transcortin
Much less is bound withalbumin
Half life (with transcortin) is1.5±2 hours
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(ii) Free form(8%) biologically active form
b. Mineralocorticoids(aldosterone)
No specific transport protein
Very weak association with albumin
Corticosterone and 11-
deoxycortiscosterone bind with CBG
Metabolism and excretion rates depend
on the presence or absence of carrier
proteins
F
TRANSPORT AND METABOLISM OFADRENAL STEROID
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A. GLUCOCORTICOIDS
(i).Reduction of Cortisol (80%) and
Corticosterone, 11 deoxycortisol
(20%) to dihydro and tetrahydro
metabolites
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METABOLISM AND EXCRETION OFADRENAL STEROID
(ii) Conjugation with glucoronoid and sulfate(iii) These modifications take place in liver
and convert these to water solublecompounds
(iv) Most of these are reabsorbed by enterohepatic circulation
(v) All there are excreted via
A. 70 % in urine
B. 20 % in fecesC. 10 % via skin
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B. Mineralocorticoids
Excreted in urine very rapidly in theform of tetrahydroaldosterone & 3-glucoronoid which are formed inliver
C. Androgens
DHEA and androstenedione as 17-keto compounds
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THANKS