Download Biochemistry Objectives 48

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, 21hydroxylase, 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 5,4isomerase, 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