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Cholesterol and the steroid hormones part 2: biosynthesis
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Endocrinology Mind Map on Cholesterol and the steroid hormones part 2: biosynthesis, created by maisie_oj on 13/04/2013.
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endocrinology
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Resource summary
Cholesterol and the steroid hormones part 2: biosynthesis
Sources of cholesterol
Diet
Receptor mediated uptake uptake of LDL/HDL cholesterol from the circulation
LDL deposit cholesterol
HDL take up cholesterol from the tissues
De novo synthesis (in steroid-secreting cells)
Radioactive work established all of synthesised cholesterol's carbon atoms came from acetate
Approximately 50% of the body's cholesterol is from de novo biosynthesis
10% from the liver
15% from the intestines
Occurs in the cytoplasm and ER of steroid-secreting cells
Uses acetate as building blocks - forming acetyl-CoA
Series of steps from acetyl-CoA to build the steroid nucleus
A key enzymes in this process is HMG-CoA reductase (= rate limiting step)
An integral protein of the ER membrane
Rate limiting step of cholesterol synthesis - heavily regulated
Also a target for pharmaceutical agents (e.g. statins)
Statins contain a region that is analogous to mevaldehyde/mevalonate
Clinical trials show that statins greatly reduce blood cholesterol levels and and reduce the risk of cardiovascular disease
Regulation of HGM-CoA reductase
HMG-CoA
HMG-CoA reductase
(Mevaldehyde) -> mevalonate
->->->-> farnesyl-PP
x2 Squalene
Cholesterol
Oxidised cholesterol
+
Farnesyl-P
+
Pi
(long term regulation) - DEGRADATION of HMG-CoA reductase
(short term regulation) - INACTIVATION of HMG-CoA reductase
+
AMPK
+
High AMP (low ATP)
+
Insulin and thyroid hormones
-
Glucagon and glucocorticoids
Hormonal regulation of HMG-CoA reductase
STATINS
e.g. lovastatin, zocor etc.
Acetyl-CoA + acetoacetyl-CoA
HMG-CoA synthase
-> HMG-CoA
HMG-CoA reductase
(active site intermediate = mevaldehyde) -> mevolanate
Farnesyl-pyrophosphate (PP)
x2 Squalene
Cholesterol
2NADPH - > 2NADP(+) + HS-CoA
Cholesterol-ester stores (in steroid-secreting cells)
Steroid-secreting cells
Feature lipid droplets
Lots of SER
Mitochondria with tubular christae
Mitochondria appear circular (characteristic)
Sites of steroid synthesis
Cholesterol is stored in lipid dorplets within the cell as a cholesterol ester (Cholesterol + acetyl-CoA)
This is catalysed by ACAT (acetyl-CoA cholesterol acetyl transferase)
Acetyl-CoA + Cholesterol -> Cholesterol-ester (CE)
When cholesterol is need for steroid synthesis the reverse reaction is catalysed by; CE-hydrolase
CE -> Cholesterol + acetate
Cholesterol -> steroid biosynthesis pathway
ACAT is found in the ER
Steroidogenesis
Rate limiting step
The rate of delivery to the inner mitochondrial membrane
Early studies showed that protein synthesis inhibtion also inhibited steroidogenesis - suggesting a rapidly synthesised protein was inportant in this
Two candidates;
StAR (Steroidogenesis acute regulatory protein)
37kDa precursor in response to cAMP
Short half-life
Active at the level of the outer mitochondrial membrane
Mitochondrial importation of StAR results in the generation of the 30kDa mature StAR protein and terinates its activity
PBR (Peripheral benzodiazapine receptor
High affinity cholesterol binding protein
Located in the outer mitochondrial membrane
Abundant where outer and inner membranes contact
Mutation/down-regulation: inhibition of steroidogenesis
Deletion: lethal phenotype
PBR drug ligands affect cholesterol transport into mitochondria
Both are needed to get cholesterol across the mitochondrial membrane
StAR insertion into the outer mitochondrial membrane allows PBR to form a channel(?)
(Surprisingly) not the rate of cholesterol uptake, synthesis by the cell or the activity of the enzyme P450scc...
P450 = enzyme that catalyses the conversion of cholesterol into pregnenolone (the first step of steroidogenesis)
Enzymes of steroid biosynthesis
Mostly members of the CYP gene family
Encode cytochrome P450 enzymes - catalyse hydroxylations
Found in all steroid hormone producing and metabolising cells
Other enzymes are hydroxysteroid dehydrogenases (HSDs)
Steroidogenesis map
CHOLESTEROL
P450scc (side chain cleavage)
PREGNENOLONE
3-beta-HSD
PROGESTERONE
P450c21 hydroxylase
DEOXYCORTICOSTERONE
P450 11 beta Hydroxylase
CORTICOSTERONE
Aldosterone synthase
ALDOSTERONE
P450 17alpha hydroxylase
P450 17alpha hydroxylase
17-alpha -OH- PRENENOLONE
3-beta-HSD
17-alpha -OH- PROGESTERONE
P450c21 hydroxylase
DEOXYCORTISOL
P450 11 beta Hydroxylase
CORTISOL
P450 17alpha hydroxylase
ANDROSTENEDIONE
Aromatase
ESTRONE
17beta-HSD
ESTRADIOL
P450 17, 20 Lyase
DHEA
3-beta-HSD
17beta-HSD
TESTOSTERONE
5alpha reductase
DIHYDROTESTOSTERONE
Aromatase
Red = enzyme; green = progestogens; yellow= mineralocorticoid; blue = androgens and orange = oestrogens
In the mitochondria and SER (steroids move betwen these compartments by an unknown mechanism)
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