Cholesterol and the steroid hormones part 2: biosynthesis

maisie_oj
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Endocrinology Mind Map on Cholesterol and the steroid hormones part 2: biosynthesis, created by maisie_oj on 04/13/2013.

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maisie_oj
Created by maisie_oj over 6 years ago
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Cholesterol and the steroid hormones part 2: biosynthesis
1 Sources of cholesterol
1.1 Diet
1.1.1 Receptor mediated uptake uptake of LDL/HDL cholesterol from the circulation
1.1.1.1 LDL deposit cholesterol
1.1.1.2 HDL take up cholesterol from the tissues
1.2 De novo synthesis (in steroid-secreting cells)
1.2.1 Radioactive work established all of synthesised cholesterol's carbon atoms came from acetate
1.2.2 Approximately 50% of the body's cholesterol is from de novo biosynthesis
1.2.2.1 10% from the liver
1.2.2.2 15% from the intestines
1.2.3 Occurs in the cytoplasm and ER of steroid-secreting cells
1.2.3.1 Uses acetate as building blocks - forming acetyl-CoA
1.2.3.1.1 Series of steps from acetyl-CoA to build the steroid nucleus
1.2.3.1.1.1 A key enzymes in this process is HMG-CoA reductase (= rate limiting step)
1.2.3.1.1.1.1 An integral protein of the ER membrane
1.2.3.1.1.1.2 Rate limiting step of cholesterol synthesis - heavily regulated
1.2.3.1.1.1.2.1 Also a target for pharmaceutical agents (e.g. statins)
1.2.3.1.1.1.2.1.1 Statins contain a region that is analogous to mevaldehyde/mevalonate
1.2.3.1.1.1.2.1.1.1 Clinical trials show that statins greatly reduce blood cholesterol levels and and reduce the risk of cardiovascular disease
1.2.3.1.1.1.2.2 Regulation of HGM-CoA reductase
1.2.3.1.1.1.2.2.1 HMG-CoA
1.2.3.1.1.1.2.2.1.1 HMG-CoA reductase
1.2.3.1.1.1.2.2.1.1.1 (Mevaldehyde) -> mevalonate
1.2.3.1.1.1.2.2.1.1.1.1 ->->->-> farnesyl-PP
1.2.3.1.1.1.2.2.1.1.1.1.1 x2 Squalene
1.2.3.1.1.1.2.2.1.1.1.1.1.1 Cholesterol
1.2.3.1.1.1.2.2.1.1.1.1.1.1.1 Oxidised cholesterol
1.2.3.1.1.1.2.2.1.1.1.1.1.1.1.1 +
1.2.3.1.1.1.2.2.1.1.1.1.2 Farnesyl-P
1.2.3.1.1.1.2.2.1.1.1.1.2.1 +
1.2.3.1.1.1.2.2.1.1.1.1.3 Pi
1.2.3.1.1.1.2.2.1.1.2 (long term regulation) - DEGRADATION of HMG-CoA reductase
1.2.3.1.1.1.2.2.1.1.3 (short term regulation) - INACTIVATION of HMG-CoA reductase
1.2.3.1.1.1.2.2.1.1.3.1 +
1.2.3.1.1.1.2.2.1.1.3.1.1 AMPK
1.2.3.1.1.1.2.2.1.1.3.1.1.1 +
1.2.3.1.1.1.2.2.1.1.3.1.1.1.1 High AMP (low ATP)
1.2.3.1.1.1.2.2.1.1.4 +
1.2.3.1.1.1.2.2.1.1.4.1 Insulin and thyroid hormones
1.2.3.1.1.1.2.2.1.1.4.1.1
1.2.3.1.1.1.2.2.1.1.5 -
1.2.3.1.1.1.2.2.1.1.5.1 Glucagon and glucocorticoids
1.2.3.1.1.1.2.2.1.1.5.1.1 Hormonal regulation of HMG-CoA reductase
1.2.3.1.1.1.2.2.1.1.5.2 STATINS
1.2.3.1.1.1.2.2.1.1.5.2.1 e.g. lovastatin, zocor etc.
1.2.3.1.1.2 Acetyl-CoA + acetoacetyl-CoA
1.2.3.1.1.2.1 HMG-CoA synthase
1.2.3.1.1.2.1.1 -> HMG-CoA
1.2.3.1.1.2.1.1.1 HMG-CoA reductase
1.2.3.1.1.2.1.1.1.1 (active site intermediate = mevaldehyde) -> mevolanate
1.2.3.1.1.2.1.1.1.1.1 Farnesyl-pyrophosphate (PP)
1.2.3.1.1.2.1.1.1.1.1.1 x2 Squalene
1.2.3.1.1.2.1.1.1.1.1.1.1 Cholesterol
1.2.3.1.1.2.1.1.1.2 2NADPH - > 2NADP(+) + HS-CoA
1.3 Cholesterol-ester stores (in steroid-secreting cells)
1.3.1 Steroid-secreting cells
1.3.1.1 Feature lipid droplets
1.3.1.2 Lots of SER
1.3.1.2.1
1.3.1.3 Mitochondria with tubular christae
1.3.1.3.1 Mitochondria appear circular (characteristic)
1.3.1.3.2 Sites of steroid synthesis
1.3.2 Cholesterol is stored in lipid dorplets within the cell as a cholesterol ester (Cholesterol + acetyl-CoA)
1.3.2.1 This is catalysed by ACAT (acetyl-CoA cholesterol acetyl transferase)
1.3.2.1.1 Acetyl-CoA + Cholesterol -> Cholesterol-ester (CE)
1.3.2.1.2 When cholesterol is need for steroid synthesis the reverse reaction is catalysed by; CE-hydrolase
1.3.2.1.2.1 CE -> Cholesterol + acetate
1.3.2.1.2.1.1 Cholesterol -> steroid biosynthesis pathway
1.3.2.1.3 ACAT is found in the ER
2 Steroidogenesis
2.1 Rate limiting step
2.1.1 The rate of delivery to the inner mitochondrial membrane
2.1.1.1 Early studies showed that protein synthesis inhibtion also inhibited steroidogenesis - suggesting a rapidly synthesised protein was inportant in this
2.1.1.1.1 Two candidates;
2.1.1.1.1.1 StAR (Steroidogenesis acute regulatory protein)
2.1.1.1.1.1.1 37kDa precursor in response to cAMP
2.1.1.1.1.1.2 Short half-life
2.1.1.1.1.1.3 Active at the level of the outer mitochondrial membrane
2.1.1.1.1.1.4 Mitochondrial importation of StAR results in the generation of the 30kDa mature StAR protein and terinates its activity
2.1.1.1.1.2 PBR (Peripheral benzodiazapine receptor
2.1.1.1.1.2.1 High affinity cholesterol binding protein
2.1.1.1.1.2.2 Located in the outer mitochondrial membrane
2.1.1.1.1.2.2.1 Abundant where outer and inner membranes contact
2.1.1.1.1.2.3 Mutation/down-regulation: inhibition of steroidogenesis
2.1.1.1.1.2.4 Deletion: lethal phenotype
2.1.1.1.1.2.5 PBR drug ligands affect cholesterol transport into mitochondria
2.1.1.1.1.3 Both are needed to get cholesterol across the mitochondrial membrane
2.1.1.1.1.3.1 StAR insertion into the outer mitochondrial membrane allows PBR to form a channel(?)
2.1.2 (Surprisingly) not the rate of cholesterol uptake, synthesis by the cell or the activity of the enzyme P450scc...
2.1.2.1 P450 = enzyme that catalyses the conversion of cholesterol into pregnenolone (the first step of steroidogenesis)
2.2 Enzymes of steroid biosynthesis
2.2.1 Mostly members of the CYP gene family
2.2.1.1 Encode cytochrome P450 enzymes - catalyse hydroxylations
2.2.1.1.1 Found in all steroid hormone producing and metabolising cells
2.2.2 Other enzymes are hydroxysteroid dehydrogenases (HSDs)
2.2.3 Steroidogenesis map
2.2.3.1 CHOLESTEROL
2.2.3.1.1 P450scc (side chain cleavage)
2.2.3.1.1.1 PREGNENOLONE
2.2.3.1.1.1.1 3-beta-HSD
2.2.3.1.1.1.1.1 PROGESTERONE
2.2.3.1.1.1.1.1.1 P450c21 hydroxylase
2.2.3.1.1.1.1.1.1.1 DEOXYCORTICOSTERONE
2.2.3.1.1.1.1.1.1.1.1 P450 11 beta Hydroxylase
2.2.3.1.1.1.1.1.1.1.1.1 CORTICOSTERONE
2.2.3.1.1.1.1.1.1.1.1.1.1 Aldosterone synthase
2.2.3.1.1.1.1.1.1.1.1.1.1.1 ALDOSTERONE
2.2.3.1.1.1.1.1.2 P450 17alpha hydroxylase
2.2.3.1.1.1.1.1.2.1
2.2.3.1.1.1.2 P450 17alpha hydroxylase
2.2.3.1.1.1.2.1 17-alpha -OH- PRENENOLONE
2.2.3.1.1.1.2.1.1 3-beta-HSD
2.2.3.1.1.1.2.1.1.1 17-alpha -OH- PROGESTERONE
2.2.3.1.1.1.2.1.1.1.1 P450c21 hydroxylase
2.2.3.1.1.1.2.1.1.1.1.1 DEOXYCORTISOL
2.2.3.1.1.1.2.1.1.1.1.1.1 P450 11 beta Hydroxylase
2.2.3.1.1.1.2.1.1.1.1.1.1.1 CORTISOL
2.2.3.1.1.1.2.1.1.1.2 P450 17alpha hydroxylase
2.2.3.1.1.1.2.1.1.1.2.1 ANDROSTENEDIONE
2.2.3.1.1.1.2.1.1.1.2.1.1 Aromatase
2.2.3.1.1.1.2.1.1.1.2.1.1.1 ESTRONE
2.2.3.1.1.1.2.1.1.1.2.1.1.1.1 17beta-HSD
2.2.3.1.1.1.2.1.1.1.2.1.1.1.1.1 ESTRADIOL
2.2.3.1.1.1.2.1.2 P450 17, 20 Lyase
2.2.3.1.1.1.2.1.2.1 DHEA
2.2.3.1.1.1.2.1.2.1.1 3-beta-HSD
2.2.3.1.1.1.2.1.2.1.1.1
2.2.3.1.1.1.2.1.2.1.1.1.1 17beta-HSD
2.2.3.1.1.1.2.1.2.1.1.1.1.1 TESTOSTERONE
2.2.3.1.1.1.2.1.2.1.1.1.1.1.1 5alpha reductase
2.2.3.1.1.1.2.1.2.1.1.1.1.1.1.1 DIHYDROTESTOSTERONE
2.2.3.1.1.1.2.1.2.1.1.1.1.1.2 Aromatase
2.2.3.1.1.1.2.1.2.1.1.1.1.1.2.1
2.2.3.2 Red = enzyme; green = progestogens; yellow= mineralocorticoid; blue = androgens and orange = oestrogens
2.2.4 In the mitochondria and SER (steroids move betwen these compartments by an unknown mechanism)

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