Cholesterol Synthesis. Flashcards
Is free cholesterol found in the plasma membrane?
Yes.
In both layers.
Why is free cholesterol found in the plasma membrane?
It maintains membrane fluidity at different temperatures.
How is cholesterol usually obtained by the body?
It is normally taken in via the diet.
Can the liver synthesise cholesterol?
Yes.
Cholesterol is a key component of what digestive tool?
Bile acids.
Can the brain synthesise cholesterol?
Yes.
Why will the brain synthesise cholesterol?
As it cannot cross the blood brain barrier.
Cholesterol is used to form what hormones?
Cortisol - in the adrenal cortex.
Testosterone - testes.
Estradiol - ovaries.
Can the liver synthesise hormones?
No.
But it can alter them.
Where does cholesterol synthesis take place?
In the cytoplasm and smooth ER of liver cells.
Where in the liver cell is the enzyme HMG-CoA reductase found?
In the smooth ER.
What 3 things will regulate cholesterol synthesis?
Substrate availability and energy status.
Serum, insulin and glucagon ratios.
Pre existing cholesterol.
Why will ATP levels always be kept high in the liver?
So it can maintain essential processes such as gluconeogenesis
What hormone will activate cholesterol synthesis?
Insulin.
What is the building block that is used for cholesterol synthesis?
ACoA.
Can the ACoA that forms fatty acids be used for cholesterol synthesis?
Yes.
What is the regulatory step of cholesterol synthesis?
The 3rd step, where 3 molecules of ACoA are bonded together to make mevalonate.
What enzyme is responsible for forming mevalonate?
HMG CoA reductase.
Other than forming mevalonate, what other job can HMG CoA reductase do?
It can form ketone bodies.
How many carbons does cholesterol have?
27.
What happens in step 1 of cholesterol synthesis?
2 molecules of cytoplasmic ACoA are joined together to form acetoacetyl-CoA.
What enzyme will join 2 ACoAs to make acetoacetyl CoA?
Cytosolic thiolase.
How many carbons does acetoacetyl CoA have?
4.
How many carbons does ACoA have?
2.
What happens in step 2 of cholesterol synthesis?
Another molecule of ACoA is added to acetoacetyl-CoA to form HMG-CoA.
What enzyme will form HMG-CoA in step 2 of cholesterol synthesis?
HMG-CoA synthase.
What is the regulated step of cholesterol synthesis?
Step 3.
What happens in step 3 of cholesterol synthesis?
HMG-CoA is reduced to mevalonate and 2 NADP+ molecules are reduced.
What enzymes will statins try to inhibit?
HMG-CoA reductase.
Is the formation of mevalonate irreversible?
Yes.
What is the enzyme used, substrate, product and coenzymes used in step 3 of cholesterol synthesis?
Enzyme used. HMG-CoA reductase.
Substrate. HMG CoA.
Product. Mevalonate.
Coenzymes. 2 NADP+.
How many carbons does mevalonate have?
6.
What happens in step 4 of cholesterol synthesis?
Mevalonate is converted into 3-isopentenyl pyrophosphate in 3 reactions.
Does the conversion of mevalonate to 3-isopentenyl pyrophosphate use any energy?
Yes.
Each of the 3 reactions uses 1 ATP.
How many carbons are lost when mevalonate is converted to 3-isopentenyl pyrophosphate?
1.
What happens in step 5 of cholesterol synthesis?
3-isopentenyl pyrophosphate is isomerised to form dimethylallyl pyrophosphate.
What happens in step 6 of cholesterol synthesis?
A 3-isopentenyl pyrophosphate molecule is added to dimethylallyl pyrophsophate.
What is the name of the product formed in step 6 of glycolysis, when a 3-isopentenyl pyrophosphate molecule is added to dimethylallyl pyrophsophate.
Geranyl pyrophosphate.
How many carbons does geranyl pyrophosphate have?
10.
What happens in step 7 of cholesterol synthesis, after gernayl pyrophosphate has been formed?
Another 3-isopentenyl pyrophosphate is added to geranyl pyrophosphate.
What is formed in step 7 of cholesterol synthesis when 3-isopentenyl pyrophosphate is added to geranyl pyrophosphate?
Farnesyl pyrophosphate molecule.
What happens in step 8 of cholesterol synthesis, after farnesyl pyrophosphate has been formed?
2 farnesyl pyrophosphate molecules are combined to make a 30 carbon molecule.
What is the 30 carbon molecule called that is formed by the 2 farnesyl pyrophosphate molecules in step 8?
Squalene.
How many carbons does squalene have?
30.
How many carbons does farnesyl pyrophosphate have?
15.
What happens in step 9 of cholesterol synthesis?
The synthesis of lanosterol.
The formation of cholesterol form squalene requires a large amount of which molecule?
NADPH.
The absence of what part of cholesterol synthesis will result in microcephaly and death?
The synthesis of the double bond in ring B.
What is the quick 1st step of cholesterol synthesis?
2+2 = 4.
2 ACoA + 2 ACoA = 4 carbons.
What is the quick 2nd step of cholesterol synthesis?
4+2 = 6.
Acetoacetyl CoA + ACoA = mevalonate (6 carbons).
What is the quick 3rd step of cholesterol synthesis?
6-1 = 5.
Mevalonate is reduced to 3-isopentyl pyrophosphate = -1 carbon.
What is the quick 4th step of cholesterol synthesis?
5+5 = 10.
Dimethylallyl pyrophsophate + 3-isopentyl pyrophosphate is joined together to form geranyl pyrophosphate.
What is the quick 5th step of cholesterol synthesis?
10+5 = 15.
Dimethylallyl pyrophsophate + 3-isopentyl pyrophosphate joins to form farnesyl pyrophosphate.
What is the quick 6th step of cholesterol synthesis?
15+15 = 30.
2 farnesyl pyrophosphates are joined together to make squalene.
What is the quick 7th step of cholesterol synthesis?
30-3 = 27.
Squalene is reduced to form cholesterol.
Other than forming cholesterol, what can the 10 carbon geranyl groups be used for?
They can be used to anchor proteins in the cell membrane.
Other than forming cholesterol, what can the 15 carbon farnesyl groups be used for?
They are an important component in specific proteins.
Other than forming cholesterol, what can the 15 carbon farnesyl PP groups be used for?
They can be used to synthesise COQ.
They can also be used to synthesise dolichol-PP which is needed for the N-glycosylation of proteins.
What is the non hormonal activation of HMG CoA reductase?
Substrate availability. (HMG CoA in the cytoplasm).
What is the non hormonal inhibition of HMG CoA reductase?
Low energy.
Phosphorylation.
High cholesterol.
Why is HMG CoA reductase inhibited by low energy levels?
Because the liver needs to keep as much energy as it can for essential processes.
How is HMG CoA reductase inhibited when energy levels are low?
An AMP kinase will phosphorylate HMG CoA reductase.
How will high cytosolic levels of cholesterol inhibit HMG CoA reductase?
By stopping the transcription of HMG CoA reductase and by degrading the present enzyme.
What binding protein does not reach the nucleus when cholesterol inhibits HMG CoA reductase?
The SRE binding protein.
What does the SRE binding protein usually do when cholesterol levels are low?
It will be released from ER or nuclear membrane to bind to ACoA reductase and start cholesterol synthesis.
Which hormone will activate HMG CoA reductase?
Insulin.
How will insulin activate HMG CoA reductase?
It will de-phosphorylate the enzyme.
It will up-regulate the enzyme.
Which hormone will inhibit HMG CoA reductase?
Glucagon.
How will glucagon inhibit HMG CoA reductase?
It will phosphorylate the enzyme via the protein kinase A pathway and an AMP kinase kinase.
What will AMP kinase do?
It will phosphorylate HMG CoA reductase.
When is AMP kinase active?
When it is phosphorylated.
When is AMP kinase inactive?
When it is de-phosphorylated.
Is both cholesterol and FA synthesis activated by insulin?
Yes.
Is both cholesterol and FA synthesis inhibited by glucagon?
Yes.
Where does the majority of cholesterol and FA synthesis occur?
In the cytoplasm of the liver.
What is the substrate for cholesterol synthesis?
HMG CoA.
What is the substrate for FA synthesis?
ACoA.
What is the regulated enzyme in cholesterol synthesis?
HMG CoA reductase.
What is the regulated enzyme in FA synthesis?
Acetyl CoA carboxylase.
Will ACoA carboxylase be inhibited by phosphorylation?
Yes.
Will HMG CoA reductase be inhibited by phosphorylation?
Yes.
What molecule will non hormonally inhibit ACoA carboxylase?
Cholesterol.
What molecule will non hormonally inhibit HMG-CoA reductase?
Palmitate
The state of fatty acids is highly dependent on what?
Temperature.
The melting point of a fatty acid will increase with what?
Chain length.
Lack of double bonds.
How does cholesterol alter cell membranes at low temperatures?
Cholesterol will increase membrane fluidity by separating them to prevent close packing.
How does cholesterol alter cell membranes at high temperatures?
The steroid ring of cholesterol will decrease the fluid nature of the fatty acids and stabilise the membrane.
The outer layer of the plasma membrane is mainly composed of what 4 substances?
Phosphatidylcholine.
Sphingomyelin.
Glycosphivnglipids.
Phosphoditdylethanoline.
What is the difference between sphingomyelin and phosphatidylcholine?
They have the same polar head, but different backbones.
What is the backbone of sphingomyelin?
The phosphosphingolipid ceramide N acyl sphingosine.
Where is sphingomyelin found?
In the membranes of RBCs.
It is a major structural phospholipid in myelin in nerve fibres.
The inner layer of the plasma membrane is mainly composed of what 5 substances?
Phosphatidylethanolamine.
Phosphatidylcholine.
Phosphatidylserine.
Phosphatidylinositol.
PIP2.
What charge does phosphatidylserine have?
A negative charge.
What does phosphatidylinositol contain?
Arachidonic acid.
What can phosphatidylinositol be used to form?
PIP-2.
Where are glycoproteins found on the cell membrane?
On the outer layer of the membrane.
Where in the cell is cardiolipin found?
In the inner mitochondrial membrane.
Polar lipids in humans are divided into what 2 categories?
Phosphate containing.
Sugar Containing.
What are the characteristics of phosphate containing lipids?
Most have a glycerol backbone and are known as phospholipids.
What are the characteristics of sugar containing lipids?
Most contain a sphingosine backbone and are known as glycolipids.
Which lipid is neither a phospholipid or a glycolipid?
Sphingomyelin is a phospholipid and a glycolipid.
Why is sphingomyelin a glycolipid and a phospholipid?
As it contains a phosphate group which is bound to a sphingosine backbone.
Where are glycolipids found?
In the brain.
In the peripheral nervous tissue.
In the myelin sheaf.
Describe cerebrosides?
These have 1 sugar and 1 ceramide.
Describe globosides?
These are formed from cerebrosides and contain more sugars.
Define sulphatides?
These are globosides that contain sulphated galactosyl residues.
Describe globosides?
These are globosides that have an added N-acetyl-neuraminic-acid.
Where are globosides usually found?
In the central nervous system.
What is the structure of a glycerophospholipid?
They have a glycerol backbone that is bound to a phosphatidic acid and 2 fatty acids.
Are glycerophospholipids polar or non polar?
Polar.
What can make up the phosphatidic acid in glycerophospholipids?
Choline.
Ethanolamine.
Serine.
Inositol.
What is the structure of a sphingolipid?
These contain phosphocoline bound to ceramide.
What is the structure of a glycosphingolipids?
They an N-acyl sphingosine (ceramide) and either a cerebroside, globoside, sulphatide or gangliotide.
Where are sphingolipids often found?
In RBC membranes and in the myelin of nerve fibres.
