Cholesterol Flashcards
(31 cards)
What is cholesterol?
A steroid which is able to increase or decrease membrane stiffness depending on temperature and the nature of the membrane. It changes interactions with the cytoskeleton
How are physiological requirements for cholesterol fulfilled?
By the liver through the de novo synthesis of cholesterol from Acetyl-Co A
3 main parts of cholesterol biosynthesis
1) Synthesis of isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (cytoplasm)
2) Condensation of 6 molecules of isopentenyl pyrophosphate to form squalene (cytoplasm)
3) Cyclisation and demethylation of squalene by monooxygenases to give cholesterol. (ER)
1st reaction of cholesterol biosynthesis
condensation of two acetyl coA molecules to form acetoacetyl coA. Catalysed by beta-ketothiolase
2nd reaction of cholesterol biosynthesis
Condensation of another Acetyl CoA to form HMG-CoA. Catalysed by HMG-CoA synthase
3rd reaction of cholesterol biosynthesis
HMG-CoA reduced by 2 NADPH to give Mevalonate. Catalysed by HMG-CoA reductase
What’s special about HMG-CoA reductase?
It is under negative back control by cholesterol, bile salts and mevalonate.
4th reaction of cholesterol biosynthesis
Mevalonate (catalysed by mevalonate kinase) 5-phosphomevalonate (catalysed by phosphomevalonate kinase) 5-pyrophosphate mevalonate (catalysed by kinase) intermediate with phosphate group attached to position 3 (catalysed by phosphomevalonate decarboxylase) 3-isopentenyl pyrophosphate
In summary, mevalonate undergoes phosphorylation at positions 3 and 5 and then decarboxylation to give 3-isopentenyl pyrophosphate.
5th reaction of cholesterol biosynthesis
3-isopentenyl pyrophosphate (isopentenyl pyrophosphate isomerase) dimethylallyl pyrophosphate (geranyl transferase - condenses a unit of 3-isopentenyl pyrophosphate on) Geranyl pyrophosphate (same as above) Farnesyl pyrophosphate
6th reaction of cholesterol biosynthesis
2 farsenyl pyrophosphates condense to form squalene and two pyrophosphates
catalysed by squalene synthetase
Describe the steps to make squalene into cholesterol
There are 3 steps
1) Squalene is first reduced in the presence of oxygen to form squalene epoxide. This has a different C=C distribution priming the molecule for carbon ring fusion.
2) The enzyme squalene epoxide lanosterol cyclase catalyses the formation of lanosterol. A series of 1,2 methyl and hydride shifts along the chain of the squalene molecule allow the formation of 4 rings.
3) Lanosterol is then subsequently reduced and demethylated 3 times to form cholesterol.
What is the precursor of all 5 classes of steroid hormones? and How is it made from cholesterol?
Pregnenolone is the steroid hormone precursor.
It is made from cholesterol by the action of the enzyme desmolase.
Synthesis of Vitamin D from cholesterol
7-dehydrocholesterol
(this conversion requires ultraviolet light)
Previtamin D3
Vitamin D3 (AKA cholecalciferol) (hydroxylation) Calcitriol (this is important for calcium metabolism)
What is the major breakdown product of cholesterol? What are the two main products?
Bile salts
The primary bile salts are glycocholate and taurocholate
In which two ways is cholesterol involved with cell signalling?
1) Lipid rafts - fluctuating assemblies of cholesterol and sphingolipids within the plasma membrane, which organise processes like cell signalling by localising key proteins like cell surface receptors
2) Covalently Attaches to the N terminal of the hedgehog signalling protein (N-Hh) which limits its diffusion into tissues during embryogenesis for successful limb formation
What are lipoproteins composed of?
Lipoproteins are composed of a phospholipid bilayer that contains cholesterol and apoproteins. Packed in the core are cholesterol esters and triacylglycerols.
Types of apoproteins
Apo E
Apo B-100
Apo A-I
How are cholesterol esters synthesised?
Synthesised in the plasma by transferring the acyl group of phosphatidylcholine (lecithin) to cholesterol. Catalysed by lecithin cholesterol acyltransferase.
Why are cholesterol esters synthesised?
They are more hydrophobic than cholesterol so pack more tightly within the core of the lipoprotein
What is the alternative way of synthesising cholesterol esters? and when is this method used?
From long chain fatty acyl CoA species. The enzyme used is Acyl CoA acyl transferases. ACAT is an intracellular enzyme so acts on cholesterol taken in by endocytosis.
How are lipoproteins categorised? Give the names of the 5 lipoproteins. What enables these lipoproteins to be recognised by different cell types.
Categorised by density.
1) Chylomicrons
2) very low density lipoproteins (VLDL)
3) Intermediate density lipoproteins (IDL)
4) low density lipoproteins (LDL)
5) high density lipoproteins (HDL)
The different categories of lipoproteins have different apoprotein content which enables them to be recognised by different cell types
What is the route of chylomicrons carrying TAGs following their resynthesis in the enterocytes?
The chylomicrons travel from the lacteals of the intestine to the thoracic duct and left subclavian vein where they reach the bloodstream
Where is the enzyme lipoprotein lipase located?
On the capillary endothelial cells lining tissues like skeletal muscle, adipose and the heart.
How is lipoprotein lipase activated? what does this enzyme do? What happens to the products?
Lipoprotein lipase is activated by Apo C-II of the chylomicron. The enzyme hydrolyses the TAGs into fatty acids and glycerol. The fatty acids undergo beta oxidation. The glycerol is returned to the liver for gluconeogenesis.
