Steroidogenesis
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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. HMG-CoA. Acetate. HMG-CoA Reductase.

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Steroidogenesis

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Steroidogenesis

Steroidogenesis


Steroid hormones

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


Steroidogenesis

HMG-CoA

Acetate

HMG-CoA

Reductase

Mevalonic acid

Cholesterol


Steroidogenesis1

Steroidogenesis

  • Modification of cholesterol

    • Changes in the number of carbons

    • Location of double bond

    • Redox reaction

  • Location of steroidogenesis

    • Mitochondria

    • Cytoplasm


Steroidogenesis

  • 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


Steroidogenesis

  • 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

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


Steroidogenesis

  • Pregnenolone

    • Universal substrate for synthesis of steroids

      • Ovarian steroids

      • Testicular steroids

      • Adrenal steroids


Steroidogenesis

  • Synthesis of progesterone (P4) from P5

    • Cytosol

      • Isomer formation

      • Reduction of ketone to alcohol

      • Done by 3b-HSD (3b-hydroxysteroid dehydrogenase) and ∆5,4isomerase


Steroidogenesis

  • Alternative to synthesis of P4

    • Synthesis of 17-hydorxypregnenolone

      • Addition of hydroxyl group on C-17

      • Done by Cytochrome C P 450C17 (17a- hydroxylase)

    • Conversion of17-hydroxypregnenolone to dehydroepiandrosterone

      • Cleavage of side-chain on C17

        • Formation of C-19 steroid

        • Done by Cytochrome C P 450C17 (17a- hydroxylase)


Steroidogenesis

  • Conversion of progesterone

    • 17-hydroxyprogesterone

      • Addition of hydroxyl group on C-17

      • Done by Cytochrome C P 450C17 (17a- hydroxylase)

      • Synthesized from 17-hydroxypregnenolone

        • 3b-HSD


Steroidogenesis

  • Conversion of progestigens to androstenedione

    • Androgen precursor

    • Done by 3b-HSD (3b-hydroxysteroid dehydrogenase)

      • Same in both 17 hydroxyprogesteone and dehydroepiandrosterone


Steroidogenesis

  • 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


Steroidogenesis

  • 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


Steroidogenesis

  • Key components of steroidogenesis

    • StAR

      • Rate-limiting step of the entire process

    • Enzymes

      • P450scc

      • 3b-HSD

      • P 450C17

      • 17b-HSD

      • P450arom


Biological activity of steoroids

Biological activity of steoroids

  • Major products

    • Most potent form

      • Progesterone

      • Estradiol

      • Testosterone

        • DHT

  • Intermediates

    • Very low biological activity

      • Need to be converted


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