Transcript Slide 1
STEROIDOGENESIS NABIL BASHIR 2009 Adrenal Steroid Hormone Biosynthesis General Structural Features for the Steroid Hormones: 1. Intact four ring system (except vitamin D where the Bring 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). General Structure and Numbering Scheme Steroid hormones are classified according to their physiologic action and tissue of origin: 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: AcylCoenzyme 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. Cholesterol Side-Chain Cleavage (SCC): A "Key" Reaction in Adrenal Steroid Hormone Synthesis . All mammalian steroid hormones are formed from cholesterol via pregnenolone Subcellular Compartmentalization of Glucocorticoid Biosynthesis: Next slide 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 11deoxycorticosterone (DOC). DOC is an active (Na+-retaining) mineralocorticoid. iii) Next hydroxylation is at C11 producing corticosterone. . 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 18hydroxycorticosterone and aldosterone via Gp induced increases in IP3/Ca2+ and DAG (more next lecture...). 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 11deoxycortisol which is then hydroxylated at C11 to form cortisol. Cortisol is the most potent natural glucocorticoid hormone is humans. Adrenal steroid biosynthesis involves the shuttling of precursors between mitochondria and the ER STAR: Steroidogenic Acute Regulatory Protein (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) Proposed Mechanism of Action of ACTH in the ZF of the Adrenal Cortex : 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 (3bOHSD) (4) D5-D4-Isomerase (5) 17b-Hydroxysteroid Dehydrogenase (17bOHSD) 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. 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.