Adrenal Steroid Hormone Biosynthesis
General Structural Features for the Steroid Hormones:
Intact four ring system (except vitamin D where the B-ring has been opened).
Often contain hydroxyl side chains ----> sterols.
Hydroxyl groups are denoted b if they are oriented above the plane (solid line).
".......................................... "a 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:
The adrenal steroid hormones are synthesized from cholesterol derived mostly from the plasma (some cholesterol is synthesized in situ from acetyl-CoA).
Much of the cholesterol is esterified (by ACAT) and stored in lipid droplets.
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.
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:
Key to Figure, "Biosynthesis of Mineralo- and Gluco- Corticoids"
i) Pregnenolone is converted to progesterone by 3b-hydroxysteroid DH (3b-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.
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...).
i) 17a-Hydroxylase acts upon either progesterone or pregnenolone to form 17a- hydroxyprogesterone and/or 17a-hydroxypregnenolone.
ii) 17a-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.
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) 3b-hydroxysteroid DH and D5,4 isomerase (ER)
(3) 17a-hydroxylase (ER)
(4) 21-hydroxylase (ER)
(5) 11b-hydroxylase (Mitochondria)
Control of Glucocorticoid (Cortisol) Synthesis
Neuroendocrine Pathways in Emotional Stress Leading to Adrenal Activation
CRH: Corticotropin Releasing Hormone
POMC: Proopiomelanocortin, complex hormone
Proposed Mechanism of Action of ACTH in the ZF of the Adrenal Cortex:
Cushing's Syndrome© Dr. Noel Sturm 2015