Metabolism 8-cholesterol Flashcards
3 main steps of the biosynthesis of cholesterol
Synthesis of isopentyl pyrophosphate, an activated isoprene unit which serves as a key building block (occurs in cytoplasm).
Condensation of six molecules of isopentyl pyrophosphate to form squalene (occurs in cytoplasm).
Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (occurs in ER).
Describe the synthesis of isopentyl pyrophosphate,
Condensation of 2 acetyl-CoA molecules to form Acetoacetyl CoA.
Condensation of another Acetyl-CoA molecule to form HMG-CoA (3-hydroxy-3-methylglutarine CoA)
HMG-CoA is reduced to generate Mevalonate
Mevalonate then undergoes sequential phosphorylation at the hydroxyl groups at positions 3 and 5, followed by decarboxylation to form 3-ISOPENTENYL PYROPHOSPHATE.
How is HMG-Coa reductase inhibited
HMG-CoA reductase is under NEGATIVE FEEDBACK control by the end product CHOLESTEROL, the intermediate MEVALONATE and BILE SALTS.
Describe the synthesis of Squalene
Isopentenyl Pyrophosphate is isomerised to form Dimethylallyl pyrophosphate which then condenses twice with isopentyl pyrophosphate to form 15C Farnesyl Pyrophosphate.
Two molecules of Farnesyl Pyrosphosphate condense to form 30 Carbon Squalene and 2 molecules of pyrophosphate.
How do you get from Squalene to cholesterol
Cyclised via an intermediate called lanosterol
What is the precursor of steroid hormones and how is it formed
The precursor pregnenolone is generated from cholesterol by the action of the enzyme desmolase.
All 5 classes of steroid hormones come from pregnenolone
Bile salt synthesis from cholesterol
Cholesterol is converted by a series of reactions to primary bile salt GLYCOCHOLATE and TAUROCHOLATE.
notes:
Bile salts account for about half of the 800mg of cholesterol made each day by the liver.
What are lipid rafts
fluctuating assemblies of cholesterol and sphingolipids - they organise processes such as cell signalling by localising key proteins such as cell surface receptors.
What do lipoprotiens consist of?
Lipoproteins consist of a phospholipid monolayer containing cholesterol and proteins known as apoproteins
Packed in the core of the lipoprotein is cholesteryl ester and triacylglycerols.
Apoprotein allows the particle to be recognised by tissue.
cholesterol esters are MORE HYDROPHOBIC than cholesterol and allows them to pack more tightly within the lipoprotein core.
Describe the synthesis of cholesterol esters
Cholesteryl Ester is synthesised in the plasma from cholesterol and the acyl chain of phosphatidylcholine (lecithin).
This is catalysed by lecithin cholesterol acyltransferase (LCAT).
Alternatively, Acyl CoA cholesterol acyltransferase (ACAT) can generate cholesterol esters from a long chain fatty acyl CoA species.
ACAT is an intracellular enzyme and acts on cholesterol which has been taken in by endocytosis.
What is LIPOPROTEIN LIPASE
Located on the capillary endothelial cells which line a variety of tissues e.g. adipose, heart and skeletal muscle.
Catalyses the hydrolysis of the triacylglycerols to GLYCEROL and FATTY ACIDS.
Apoprotein C-II on the chylomicron plays a key role in activating lipoprotein lipase.
Describe HDLs
Good Cholesterol
Peripheral Tissues –> Liver
(reverse cholesterol transport).
Help LOWER total serum cholesterol
Describe LDLs
Bad Cholesterol
Prolonged elevation of LDL levels leads to atherosclerosis.
Liver —> Peripheral Tissues
> 40% of weight made up of cholesterol esters
What is Familial Hypercholesterolaemia
FH is inherited as a monogenic dominant trait.
Heterozygotes have cholesterol levels which are 2-3 times higher than in normal people.
Homozygotes are severely affected. Their serum cholesterol levels are 5 times higher than normal people.
Homozygotes can have severe atherosclerosis and coronary infarction in adolescence.
Patients with severe FH lacked functional LDL receptors
Two ways of controlling Hypercholesterolaemia
HMG-CoA Reductase Inhibitors:
AKA Statins
Lovastatin is a competitive inhibitor of HMG-CoA
Reductase
Resins or Sequestrants:
These bind or sequester (isolate or hide away) bile
acid-cholesterol complexes preventing their
reabsorption by the intestine.
It lowers LDL levels and raises HDL levels.
