Cholesterol Flashcards
How is cholesterol structured?
Steroid composed of 27 carbon atoms
Has cyclic rings with hydrophobic tail
Steroid ring structure is planar
Apart from hydroxyl group at position 3, molecule is very hydrophobic and consists of only H and C atoms
Why is cholesterol important?
Vital component in cell membranes- more than 90% of cholesterol in our bodies is found in cell membranes
Cholesterol can increase and decrease membrane stiffness depending on temperature and nature of membrane
What are the 3 main parts which make up the cholesterol synthesis pathway?
- Synthesis of isopentyl pyrophosphate- an activated isoprene
- Condenstation of 6 molecules of isopentyl pyrophosphate to form squalene
- Cyclisation and demethylation of squalene by monooxygenases to give cholesterol
What happens in the 1st step in the synthesis of isopentyl pyrophosphate and where does it occur?
occurs in cytoplasm
2 molecules of acetyl CoA condense to form acetoacetyl CoA
Catalysed by beta-ketothiolase
What happens in the 2nd step in the synthesis of isopentyl pyrophosphate?
Another molecule of acetyl CoA condenses to form 3-hydroxy-3-methyl-glutonyl (HMG- CoA)
this reaction is catalysed by HMG-CoA synthase
What happens in the 3rd step of synthesis of isopentyl pyrophosphate?
HMG- CoA reductase reduces HMG-CoA to give mevalonate
NADPH is used as a source of reducing power for biosynthetic reactions
HMG-CoA reductase is under negative feedback control by cholesterol, mevalonate and bile salts
What’s the 4th step in the synthesis of isopentyl pyrophosphate?
Mevalonate undergoes sequential phosphorylation at hydroxyl groups at position 3 and 5
This is followed by decarboxylation to form isopentyl pyrophosphate (isopentyl PP) which is 5 carbon
This activated isoprene unit is the main building block for cholesterol synthesis
Whats an important role of isoprene?
Isoprene unit gives lipophilicity to biomolecules
Dolichol phosphate is a specialised lipid molecule located in ER membrane and involved in N-linked glycosylation of proteins
How do proteins gain affinity for lipid bilayers?
Proteins can undergo lipid modifications such as prenylation (addition of farnesyl or a geranylgeranyl) which gives then affinity for lipid bilayers
The same lipophilic properties of isoprene unit confines ubiquinone to inner membrane of mitochondria
How is squalene formed?
Occurs in cytoplasm
Dimethylallyl pyrophosphate is produced from isopentyl PP via isomeriasation reaction
This can condense with a unit of isopentyl PP to form geranyl pyrophosphate
2 condensation reactions occur where isopentyl PP is added to dimethylallyl pyrophosphate and grows the chain to farnesyl pyrophosphate
2 farnesyl PP condense to from squalene plus 2 molecules of pyrophosphate
How is cholesterol formed in the last step?
Occurs in ER
Squalene reduced in presence of O2 and NADPH to form squalene epoxide which has different CC bond distributions
Enzyme squalene epoxide lanosterol-cyclase catalyses formation of lanosterol
A series of 1,2-methyl groups and hydride shifts along chains of squalene result in formation of the 4 rings
What happens to lanosterol?
Its reduced and 3 methyl units are removed to generate cholesterol
This takes place by 19 steps
How are bile salts synthesised from cholesterol?
Bile salts are major breakdown products of cholesterol
Cholesterol can be converted by series of reactions into the primary bile salt glycocholate and also taurocholate
How are steroid hormones synthesised?
Made from cholesterol
The precursor pregnenolone is generated from cholesterol by enzyme desolate
What are the 5 classes of hormones that come from pregnenolone?
Progestogens which give rise to:
Glucocorticoids
Mineralocorticoids
Androgens which give rise to oestrogen’s
