metabolism of steroids pavla balínová. cholesterol is a maternal molecule of all steroids in human...
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Metabolism of steroids
Pavla Balínová
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
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
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
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
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.
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.
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.
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.
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
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)
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
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.
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
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.
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.
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
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.
Male sex hormones produced in testes
cholesterol
pregnenolone
progesterone DHEA
androstenedione
hydrogenation at position 17 Leydig cells (testes)
testosterone
dihydrotestosterone
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.
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.
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
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
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
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
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