Metabolism of steroids

1. Metabolism of steroids Pavla Balínová

2. 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

3. Cholesterol structure „free“ cholesterol cholesterol ester 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.

4. 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

5. 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

6. 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.

7. 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.

8. Formation of isopentenyl diphosphate • phosphorylation of mevalonate (2 ATP) → mevalonyl diphosphate → decarboxylation with consumption of ATP → isopentenyl diphosphate („ active isoprene“) Figure was assumed from bookT. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

9. 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 bookT. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

10. 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

11. 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)

12. 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

13. 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 bacteria in intestine ● secondary bile acids: deoxycholic and lithocholic function: emulsification of lipids in intestine → digestion and absorption Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical Correlations, 4th ed., Wiley‑Liss, Inc., New York, 1997.

14. 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

15. 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.

16. 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.

17. 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

18. 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.

19. Male sex hormones produced in testes cholesterol pregnenolone progesterone DHEA androstenedione hydrogenation at position 17 Leydig cells (testes) testosterone dihydrotestosterone

20. 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.

21. 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.

22. 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

23. Lipoproteins = carriers of lipids and cholesterol TAG cholesterol ester phospholipid cholesterol apolipoprotein Figure was assumed from http://www.lce.hut.fi/research/sysbio/biospectroscopy/lipoprotein/

24. Lipoproteins

25. Concentration of lipoproteins in serum • HDL up to 2.6 mmol/L („good“ cholesterol) • LDL up to 3.9 mmol/L („bad“ cholesterol) • Total cholesterolup 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

26. 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