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STEROIDOGENESIS NABIL BASHIR 2009. Adrenal Steroid Hormone Biosynthesis General Structural Features for the Steroid Hormones: 1.Intact four ring system.

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Presentation on theme: "STEROIDOGENESIS NABIL BASHIR 2009. Adrenal Steroid Hormone Biosynthesis General Structural Features for the Steroid Hormones: 1.Intact four ring system."— Presentation transcript:

1 STEROIDOGENESIS NABIL BASHIR 2009

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3 Adrenal Steroid Hormone Biosynthesis General Structural Features for the Steroid Hormones: 1.Intact four ring system (except vitamin D where the B- ring has been opened). 2.Often contain hydroxyl side chains ----> sterols. Hydroxyl groups are denoted β if they are oriented above the plane (solid line). 3." "α if they are oriented below the plane (dashed line).

4 General Structure and Numbering Scheme

5 Steroid hormones are classified according to their physiologic action and tissue of origin:

6 Biosynthesis of the Adrenal Steroid Hormones: 1.The adrenal steroid hormones are synthesized from cholesterol derived mostly from the plasma (some cholesterol is synthesized in situ from acetyl-CoA). 2.Much of the cholesterol is esterified (by ACAT: Acyl- Coenzyme A:Cholesterol Acyltransferase ) and stored in lipid droplets. 3.Upon stimulation of the adrenal zona fasciculata (ZF) by ACTH (adrenocorticotropic hormone) (cAMP second messenger), or the adrenal zona glomerulosa (ZG) by angiotensin II (IP3 / Ca2+ and DAG) > an esterase is activated and the free cholesterol formed is transported into the mitochondria. 4.In the mitochondria a cyctochrome P-450 cleavage enzyme (P-450scc or 20,22-lyase) converts cholesterol to pregnenolone.

7 Cholesterol Side-Chain Cleavage (SCC): A "Key" Reaction in Adrenal Steroid Hormone Synthesis

8 . All mammalian steroid hormones are formed from cholesterol via pregnenolone Subcellular Compartmentalization of Glucocorticoid Biosynthesis: Next slide

9 Key to Figure, "Biosynthesis of Mineralo- and Gluco- Corticoids" i) Pregnenolone is converted to progesterone by 3β-hydroxysteroid DH (3 β -OHSD) and D5-D4 isomerase. ii) Progesterone is hydroxylated at C21 to form 11- deoxycorticosterone (DOC). DOC is an active (Na+-retaining) mineralocorticoid. iii) Next hydroxylation is at C11 producing corticosterone..

10 Key to Figure, "Biosynthesis of Mineralo- and Gluco- Corticoids iv) 18-Hydroxylase acts on corticosterone to form 18-hydroxycorticosterone. v) The alcohol is oxidized to an aldehyde forming aldosterone. This conversion is regulated by renin-angiotensin and K+. Concentration of receptors is "up-regulated" by high K+ and "down-regulated" by low K+. Angiotensin II stimulates the conversion of cholesterol to pregnenolone, and corticosterone to 18- hydroxycorticosterone and aldosterone via Gp induced increases in IP3/Ca2+ and DAG (more next lecture...).

11 Key to Figure, "Biosynthesis of Mineralo- and Gluco- Corticoids i) 17α-Hydroxylase acts upon either progesterone or pregnenolone to form 17 α - hydroxyprogesterone and/or 17 α - hydroxypregnenolone. ii) 17 α -hydroxyprogesterone is hydroxylated at C21 to form 11- deoxycortisol which is then hydroxylated at C11 to form cortisol. Cortisol is the most potent natural glucocorticoid hormone is humans.

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13 Adrenal steroid biosynthesis involves the shuttling of precursors between mitochondria and the ER STAR: Steroidogenic Acute Regulatory Protein

14 (1) P-450scc / 20,22-lyase (Mitochondria) (2) 3 β-hydroxysteroid DH and D5,4 isomerase (ER) (3) 17 α -hydroxylase (ER) (4) 21-hydroxylase (ER) (5) 11 β -hydroxylase (Mitochondria)

15 Proposed Mechanism of Action of ACTH in the ZF of the Adrenal Cortex :

16 Sex Steroid Hormone Biosynthesis and Action Testicular Androgens: A.The conversion of pregnenolone to testosterone requires the action of 5 enzymes, all found in the ER of the testes cells. B.The conversion of pregnenolone to testosterone is referred to as the "Progesterone Pathway": (1) 17a-Hydroxylase (2) C17,20 Lyase (3) 3 β -Hydroxysteroid Dehydrogenase (3b- OHSD) (4) D5-D4-Isomerase (5) 17b-Hydroxysteroid Dehydrogenase (17b- OHSD)

17 Adrenal Androgen (Testosterone) Biosynthesis: Dihydrotestosterone (DHT), is the most potent androgen, it is formed from testosterone, by the reduction of the A ring through the action of the enzyme 5α-Reductase. The testes also produce 17 β -estradiol, the female sex hormone in small amounts, but most of the estrogens produced by the male are derived from peripheral aromitzation of testosterone.

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19 Ovarian Sex Steroid Hormones: Biosynthesis of Estrogens: The ovaries are bifunctional organs that produce both estrogens and progestins. The most active naturally occurring hormones of these classes are 17β-estradiol (E2) and progesterone.

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