Biosynthesis of steroid hormones

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BIOSYNTHESIS OF STEROIDHORMONES

DR. SUMREENA MANSOOR

ASSISTANT PROF OF BIOCHEMISTRY



` Chemical nature of the adrenal

hormones

` Outline the steps involved in steroid

biosynthesis in adrenal cortex` Transport of adrenocortical steroids

` Adrenocortical hormone metabolism



3

INTRODUCTION

Introduction

Structure, Nomenclature, Synthesis

Adrenocorticoids

Glucocorticoids, Mineralocorticoids

Male Sex Hormones

Androgens Female Sex Hormones

Estrogens and Progestins



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)



A SPECIAL NOMENCLATURE DESCRIBES THE

CHEMISTRY OF STEROIDS

COMMON C-17 COMPOUND(CYCLOPENTANOPERHYDROPHENANTHREIN

RING)



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




STRUCTURES OF STEROIDSStructure and Nomenclature of the Steroid Side-chain

CH3

CH3

CH3

CH3

CH3

20

21

22

23

24 25

26

27



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



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



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




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.)



GLUCOCORTICOID BIOSYNTHESIS



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



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



(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



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




Pregnenolone

Cytoplasmic 3 -Of DH

4,5

ISOMERASEProgesterone

In Zona glomerulosa Cytoplasmic 21 ±HYDROXYLASE

MITOCHONDRIAL 11 - HYDROXYLASE

MITOCHONDRIAL 18- HYDROXYLASE

Aldosterone



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




Pregnenolone

Cytoplasmic 17 ±HYDROXYLASE17 -Hydroxypregnenolone

In Zona reticularis Cytoplasmic 2C

Side chain cleavage

Dehydroepiandrosterone



DHEA acts as prohormone

converted to testosterone (the most

Potent androgen)

ANDROGEN SYNTHESIS



Pathway for formation of androgens in the adrenal cortex.

Pregnenolone D EA AndrostenedionAndrostenedione



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



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.



` Congenital adrenal hyperplasia

Most common in various forms:

` 3-hydroxysteroid dehydrogenase



3-hydroxysteroid dehydrogenase

No Glucocorticoids, Mineralocorticoids,

Active androgen and estrogenSalt excretion in urine

Female like genitalia



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



11-hydroxylase

Mineralocorticoids and glucocorticoidsabsent

Deoxycorticosterone causes fluidretention

Excessive Androgen masculinization of external genitalia



` Autoimmune destruction of theadrenal cortex is cause by animmune reaction against the

enzyme 21-hydroxylase



` Some medications interferewith steroid synthesis

enzymes (e.g. ketoconazole),while others accelerate thenormal breakdown of hormones by the liver (e.g.rifampicin, phenytoin)



.` In adrenal Cushing's, excess Cortisol

is produced by adrenal gland tumors,hyperplastic adrenal glands, or

adrenal glands with nodular adrenalhyperplasia.



A. Secretion of steroidhormones

Little storage and releasedinto plasma when made Cortisol release by ACTH

release



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



(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



A. GLUCOCORTICOIDS

(i).Reduction of Cortisol (80%) and

Corticosterone, 11 deoxycortisol

(20%) to dihydro and tetrahydro

metabolites



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



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



THANKS

Biosynthesis of steroid hormones

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