62 Steroid hormone biosynthesis Flashcards
What is the precursor of all steroids?
Cholesterol
What is the distribution of cholesterol?
- Membrane lipid:
• Regulator of membrane fluidity - Plasma:
• Associated with apoproteins, triacylglycerols and phospholipids in various types of micellular structures called lipoproteins - Steroid-secreting endocrine cells:
• Cytosolic lipid droplets as cholesterol esters
Cholesterol biosynthesis?
- Liver synthesises cholesterol de novo from acetyl CoA in a multi-step process that occurs in SER and cytosol
- Rate-limiting step is conversion of HMG-CoA –> mevalonate by HMG-Coa reductase
Which major classes of plasma lipoproteins contain the highest % if cholesteryl esters (core)?
IDL (30%)
LDL (35-40%)
Where are the plasma lipoproteins made?
- Chylomicrons - gut
* VLDL, IDL, LDL, HDL - liver
Cholesterol metabolism - exogenous pathway?
- Dietary cholesterol and fatty acids are absorbed
- Triglycerides are formed in the intestinal cell from free fatty acids and glycerol and cholesterol is esterified
- Triglycerides and cholesterol combine to form chylomicrons
- Chylomicrons enter the circulation and travel to peripheral sites
- In peripheral tissues, free fatty acids are released from the chylomicrons to be used as energy, converted to triglyceride or stored in adipose
- Remnants are used in the formation of HDL (taken up by liver)
Cholesterol metabolism - endogenous pathway?
- VLDL is formed in the liver from triglycerides and cholesterol esters
- These can be hydrolyzed by lipoprotein lipase to form IDL or VLDL remnants
- VLDL remnants are cleared from the circulation or incorporated into LDL
- LDL particles contain a core of cholesterol esters and a smaller amount of triglyceride
- LDL is internalized by hepatic and nonhepatic tissues
- In the liver, LDL is converted into bile acids and secreted into the intestines
- In non hepatic tissues, LDL is used in hormone production, cell membrane synthesis, or stored
- LDL is also taken up by macrophages and other cells which can lead to excess accumulation and the formation of foam cells which are important in plaque formation
Uptake of cholesterol by receptor mediated endocytosis and synthesis of steroid hormones
- Binding of LDL to receptors (receptor mediated endocytosis) of cells aggregates Clathrin to binding site on inside of cell. These form sphere vesicle coating around LDL inside the cell
- The receptors and clathrins break down leaving the lipoprotein to split into AAs, cholesterol and FFAs
- Cholesterol then going on to form pregnenolone (aldosterone, cortisol, estradiol, testosterone)
The cholesterol needed as the starting material in the synthesis of steroid hormones come from which 2 sources?
- ~80% taken up as LDL particles via receptor-mediated endocytosis
- Cell synthesis the remaining (20%) cholesterol de novo from Acetyl CoA
3 main physiological roles of cholesterol?
- Component of cell (plasma) membranes
• Decreases membrane fluidity
• Decreases physical permeability to charged/polar compounds associated with the formation of lipid rafts - Precursor for the production of bile salts
• Uptake of fats and fat-soluble vitamins in GIT - Precursory for all steroid hormones
• e.g. Glucocorticoids, mineralocorticoids and sex steroids
Describe the biosynthesis of steroid hormones?
- Cholesterol esters (catalysed by chol. ester hydrolase) –> cholesterol
- Cholesterol forms pregnenolone (side chain cleavage by desmolase) which then forms hormones via enzymatic processing in mitochondria, SER
- Steroid hormones: Progesterone, estradiol, testosterone, cortisol, aldosterone
Describe the biosynthesis of adrenal steroids?
- Synthesis of adrenal steroids (mineralocorticoid aldosterone and glucocorticoid cortisol) from cholesterol
- Enzymes located in SER or mitochondria
- Side-chain cleavage enzyme that produces pregnenolone is 20, 22 desmolase
- If the synthesis of cortisol is prevented by any one of several dysfunctional enzymes, other steroid products might be produced in excess
- e.g. A block in the 21 alpha-hydroxylase will diminish production of both cortisol and aldosterone and increase production of the sex steroids
Examples of cytochrome P-450 enzymes involved in steroidogenesis?
- Cholesterol side chain cleavage
- 11-Beta-Hydroxylase
- 17-Alpha-Hydroxylase
- 17, 20- Desmolase
- 21-Alpha-Hydroxylase
- Aldosterone synthase
- Aromatase
• 57 different P-450 enzymes in human genome
What does aromatase (P-450arom) do?
Catalyses a reaction essential fort eh production of oestrogens
The enzymes required for the biosynthesis of adrenal steroids (aldosterone and cortisol), where are they found?
SER and mitochondria
What are the different layers of the adrenal gland, from outer to inner?
- Capsule
- Cortex
• Zona glomerulosa
• Zona fasciculata
• Zona reticularis - Medulla