metabolism of steroids pavla balínová. cholesterol is a maternal molecule of all steroids in human...
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Metabolism of steroids
Pavla Balínová
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Cholesterol
• is a maternal molecule of all steroids in human body
• is a starting molecule for synthesis of bile acids and steroid hormones (sex hormones, gluco- and mineralocorticoids)
• is a component of plasma membranes
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Cholesterol structure
Figures were assumed from a book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
„free“ cholesterol cholesterol ester
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Cholesterol biosynthesis
• organ location: liver, intestine, skin, adrenal cortex• subcellular location: smooth endoplasmic reticulum• amount: about 1 g daily = endogenous cholesterol, about 0,3 g of cholesterol is taken up from food per day (exogenous cholesterol)● regulatory enzyme: HMG CoA reductase
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Sections of cholesterol biosynthesis
• formation of mevalonate from acetyl-CoA• formation of isopentenyl diphosphate („active
isoprene“) from mevalonate• formation of squalene from 6 units of
isopentenyl diphosphate• formation of cholesterol
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Synthesis of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
2x acetyl-CoA → acetoacetyl-CoA
+ acetyl-CoA HMG-CoA
Figure was byl assumed from book T. M. Devlin et al.: Textbook of Biochemistry
With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Formation of mevalonate
• reduction of HMG-CoA with the help of NADPH + H+ to mevalonate
• key regulatory enzyme: HMG-CoA reductase
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry
With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Formation of isopentenyl diphosphate
• phosphorylation of mevalonate (2 ATP) → mevalonyl diphosphate → decarboxylation with consumption of ATP → isopentenyl diphosphate („ active isoprene“)
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry
With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Formation of squalene
• squalene is synthesized by series of reactions (intermediates are geranyl diphosphate and farnesyl diphosphate
• reducting agent is NADPH + H+
• squalene contains 30 C atoms
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Formation of cholesterol
• squalene is cyclized with consumption of O2 and NADPH + H+ → lanosterol → 3 methyl groups are cleaved → cholesterol
Figure was assumed from http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm
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Regulation of cholesterol biosynthesis
Regulatory enzyme HMG CoA reductase• hormonal stimulation by insulin and
triiodotyronine, glucagon inhibits the enzyme• glucagon → ↑ cAMP → phosphorylation of
enzyme → inhibition• insulin → ↓ cAMP → dephosphorylation of
enzyme → activation● cholesterol acts as a repressor of transcription● exogenous cholesterol (from food) inhibits the
enzyme• competitive inhibitors – drugs e.g. lovastatin
(structure similar to mevalonate)
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Metabolic fates of cholesterol
What happens with synthesized cholesterol??
Esterification with help of lecithine:cholesterol acyltransferase (LCAT) → transfer of acyl of FA on –OH group of cholesterol in position 3
Cholesterol synthesized in liver:-half-life (days) → about 75% is converted into bile acids
Cholesterol synthesized in skin:→ conversion into 7-dehydrocholesterol → vitamin D (calcitriol)
Transport of cholesterol into adrenal cortex and gonads →steroid hormones
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Bile acids
• a way to get off cholesterol• are formed from cholesterol in the liver and they are excreted into a bile• primary bile acids:cholic and chenodeoxycholic
bacteriain intestine● secondary bile acids:deoxycholic and lithocholicfunction: emulsification of lipids in intestine → digestion and absorptionFigure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Cholesterol as a source of steroid hormones
• cholesterol is a metabolic precursor of all steroid hormones in human body
• number of C atoms is changing during synthesis of hormones: from 27 to 21, 19 or 18
• adrenal cortex and gonads
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Hormonal stimulation of biosynthesis of steroid hormones
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Adrenal steroid hormones
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Adrenal steroid hormones
• Cholesterol → removal of 6 C atoms from side chain → pregnenolone (21 C)
progesterone (21 C)hydroxylation hydroxylation in positions 21 and 11 in positions 17, 21
and 11
aldosterone (21 C) cortisol (21 C) mineralocorticoids glucocorticoids
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Male sex hormones produced in adrenal cortex
• in zona reticularis: cholesterol → pregnenolone → DHEA (dehydroepiandrosterone) → androstenedione
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Male sex hormones produced in testes
cholesterol
pregnenolone
progesterone DHEA
androstenedione
hydrogenation at position 17 Leydig cells (testes)
testosterone
dihydrotestosterone
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Testosterone
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Female sex hormones
• Progesterone• Testosterone → removal of 18th C atom and aromatisation → estradiol (18 C)Aromatase is located in ovaries and adipose tissue:androgens → estrogens
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.
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Degradation of steroid hormones
• sterane skeleton is very stable and it is unable to destroy it
• reduction is included in inactivation of steroids (hydrogenation of double bond) in ring A
• inactivation reactions occur in liver• conjugation with glucuronic acid or
sulphuric acid• formed conjugates are excreted with urine
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Lipoproteins = carriers of lipids and cholesterol
Figure was assumed from http://www.lce.hut.fi/research/sysbio/biospectroscopy/lipoprotein/
cholesterol ester
cholesterol
TAG
apolipoprotein
phospholipid
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type source most component
importantapolipoprote
ins
they transport mainly
chylomicrons
intestine
TAG B-48, C-II, E TAG from food intoextrahepatal tissues
VLDL liver TAG C-II, B-100 recently synthesized TAG into tissues
IDL VLDL cholesterol esters,TAG, phospholipids
B-100 remnants of VLDL into tissues
LDL VLDL cholesterol esters
B-100 cholesterol into tissues
HDL liver cholesterol esters, phospholipids
A-I, E, C-II cholesterol from tissues into liver
Lipoproteins
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Concentration of lipoproteins in serum
• HDL up to 2.6 mmol/L („good“ cholesterol)• LDL up to 3.9 mmol/L („bad“ cholesterol)• Total cholesterol up to 5.0 mmol/L
Reference values depend on an age, sex and diet.
Values were assumed from Department of biochemistry and pathobiochemstry 3. LF UK and FNKV
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Is it possible to influence the LDL level in blood?
• decrease of LDL: diet with higher content of unsaturated FA, estrogens, intake of a small amount of an alcohol, drugs (statins)
• increase of LDL: surfeit (mainly diet with higher content of animal fats), deficit or mutation of LDL receptors, diabetes, intake of a high amount of alcohol, smoking
• prevention of atherosclerosis: antioxidants (vit. C and E), fiber