Biochemistry Objectives 48 - University of Arizona
Biochemistry Objectives 48
1. Function, regulation, and significance of:
a. Cholesterol esterase: cholesterol esterase catalyzes the conversion of cholesterol ester to cholesterol in the cytoplasm, and is activated by angiotensin II (via Gq) in the zona glomerulosa or by ACTH (via Gs) in the zona fasciculata/reticularis.
b. StAR: StAR transports cholesterol from the cytoplasm into the intermembrane space of the mitochondria and is activated by ACTH via cAMP induction of StAR production and PKA phosphorylation to induce maximal activity.
c. P-450scc: P-450scc cleaves cholesterol to produce pregnenolone on the inner mitochondrial membrane, and is activated by angiotensin II (via Gq) in the zona glomerulosa or by ACTH (via Gs) in the zona fasciculata/reticularis.
2. Synthesis of aldosterone in the zona glomerulosa: synthesized from pregnenolone conversion to progesterone (via 3(-OHSD and (5,4 isomerase) followed by conversion to 11-DOC (via 21-hydroxylase) and final conversion to aldosterone (via 11(-hydroxylase and 18-hydroxylase)
Enzyme specific to zona glomerulosa: 18-hydroxylase
Enzyme specific to zona fasiculata/reticularis: 17-hydroxylase
3. Synthesis of cortisol in the zona fasiculata: synthesized from pregnenolone conversion to progesterone (via 3(-OHSD and (5,4 isomerase) followed by conversion to 17(-hydroxyprogesterone (via 17-hydroxylase) which is then convertd to 11-deoxycortisol (via 21-hydroxylase) and finally converted to cortisol (via 11(-hydroxylase)
Shuttling between mitochondria and smooth ER: the conversion of cholesterol to pregnenolone occurs in the mitochondria, and then the conversion of pregnenolone to 11-deoxycortisol occurs in the smooth ER. The final conversion of 11-deoxycortisol to cortisol occurs in the mitochondria
4. Stress reaction:
a. Epinephrine (acute): during acute stress, the sympathetic nervous system activates epinephrine to mobilize glucose from glycogen
b. Glucocorticoids (chronic): during chronic stress, the hypothalamus releases CRH, which (via Gs activity) causes the release of POMC. POMC contains the signal for ACTH, and ACTH release causes an increase in cortisol.
c. Endorphins (analgesic): from CRH stimulation, POMC also contains the signal (-lipotropin which can be converted to (-endorphin. (-endorphin causes analgesic effects by lowering cAMP in organ systems like the GI tract (via Gi).
5. Proteins affected by ACTH: increases activity of cholesterol esterase, StAR, and P-450scc (all in the cortisol synthesis pathway).
6. Pathophysiology of congenital adrenal hyperplasia:
a. Defective enzymes: any enzyme in either the glucocorticoid or mineralocorticoid pathway; StAR, 3(OH-SD or (5,4-isomerase, 21-hydroxylase, 11(-hydroxylase, 18-hydroxylase (aldosterone synthase), or 17(-hydroxylase.
b. Excess ACTH: problem with the glucocorticoid receptor, and a subsequent increase in glucocorticoid release (via ACTH)
c. Excess angiotensin II: problem with the mineralocorticoid receptor, and subsequent increase in mineralocorticoid release (via angiotensin II)
d. Steroids eliciting:
• Virilization: glucocorticoid receptor defect, 21-hydroxylase, 11(-hydroxylase, and mildly with 3(OH-SD or (5,4-isomerase (any pathway that diminishes cortisol production but leaves a pathway to testosterone production will cause virilization)
• Salt loss: mineralocorticoid receptor defect, StAR, 3(OH-SD or (5,4-isomerase, 21-hydroxylase, aldosterone synthase (18-hydroxylase and 11(-hydroxylase)
e. Treatment: treatment should be administered in the form of the deficient corticosteroid. If a patient cannot synthesize glucocorticoids, then glucocorticoid supplementation is advised. If a patient cannot synthesize mineralocorticoids, then mineralocorticoid supplementation is advised. If a patient cannot synthesize either corticosteroid, then administration of both glucocorticoids and mineralocorticoids is advised.
• Note: remember that DOC is a weak mineralocorticoid that often causes hypertension due to salt retention
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