Transcript Steroidogenesis - Delta State University

Steroidogenesis
Steroid hormones
• Cholesterol derivative
– Dietary source
• Carried in blood as a part of lipoproteins
– Synthesized by liver
– Receptor-mediated uptake by the cell
– De novo synthesis
• Cells produce their own cholesterol
• Acetate as a source
Acetate
HMG-CoA
HMG-CoA
Reductase
Mevalonic acid
Cholesterol
Steroidogenesis
• Modification of cholesterol
– Changes in the number of carbons
– Location of double bond
– Redox reaction
• Location of steroidogenesis
– Mitochondria
– Cytoplasm
• Mitochondria
– Site of side-chain cleavage
• Reduction in the number of carbons
– Transport of cholesterol
• First rate-limiting step
• Regulated by steroid acute transport regulate
protein (StAR)
– Channel protein
• StAR protein
– Transport channel
– Regulation of activity
• cAMP dependent
– Phospholyration
– Synthesis
– Loss of StAR
• 86 % reduction in steroid hormone synthesis
– Basal steroidogenesis
Side-chain cleavage
• From 27-C molecule
to 21-C molecule
– Mitochondira
– Synthesis of
pregnenolone (P5)
– Done by the P450scc
• Cytochrome C P450
enzyme superfamily
• Pregnenolone
– Universal substrate for synthesis of steroids
• Ovarian steroids
• Testicular steroids
• Adrenal steroids
• Synthesis of progesterone (P4) from P5
– Cytosol
• Isomer formation
• Reduction of ketone to alcohol
• Done by 3b-HSD (3b-hydroxysteroid dehydrogenase) and
∆5,4isomerase
• Alternative to synthesis of P4
– Synthesis of 17-hydorxypregnenolone
• Addition of hydroxyl group on C-17
• Done by Cytochrome C P 450C17 (17ahydroxylase)
– Conversion of 17-hydroxypregnenolone to
dehydroepiandrosterone
• Cleavage of side-chain on C17
– Formation of C-19 steroid
– Done by Cytochrome C P 450C17 (17a- hydroxylase)
• Conversion of
progesterone
– 17hydroxyprogesterone
• Addition of hydroxyl
group on C-17
• Done by Cytochrome C
P 450C17 (17ahydroxylase)
• Synthesized from 17hydroxypregnenolone
– 3b-HSD
• Conversion of
progestigens to
androstenedione
– Androgen precursor
– Done by 3b-HSD (3bhydroxysteroid
dehydrogenase)
• Same in both 17
hydroxyprogesteone and
dehydroepiandrosterone
• Synthesis of androgens
– Conversion of androstenedione
• Testosterone
• Done by 17b-HSD
– Conversion of testosterone
• Dihydrotestosterone
– Occurs in peripheral tissues by 5a-reductase
– More biologically active
• Synthesis of estorgen
– C-19 to C-18 steroid
– Aromatization
• A ring of the sterol ring
• Done by P450arom (aromatase/CYP 19)
– Side-chain on C-17
• Hydroxyl group
– Estradiol
• Ketone group
– Estrone
• Key components of steroidogenesis
– StAR
• Rate-limiting step of the entire process
– Enzymes
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P450scc
3b-HSD
P 450C17
17b-HSD
P450arom
Biological activity of steoroids
• Major products
– Most potent form
• Progesterone
• Estradiol
• Testosterone
– DHT
• Intermediates
– Very low biological activity
• Need to be converted