Biochem Cholesterol Flashcards
Where is cholesterol synthesized
Liver (50%)
Steroid hormone-producing organs
All of the carbon atoms of cholesterol are derived from ___
Acetyl CoA
___ catalyze the condensation of 2 acetyl CoA molecules to form one molecule of acetoacetyl CoA.
A third molecule of acetyl CoA is added by ___ to form ___
Cytosolic thiolase
HMG-CoA synthase
3-hydroxy-3-methylglutaryl-CoA
HMG-CoA is reduced to ___ by ___
- this enzyme is a major control point for cholesterol synthesis
- it is inhibited by ___
Mevalonate
HMG-CoA reductase
Statins
HMG-CoA reductase is embedded in the ___
ER
4 steps of the formation of isopentenyl diphosphate (an active isoprenoid unit)
1-3. Sequential phosphorylation by 3 kinases (uses 3 ATP)
4. Decarboxylation
Squalene is formed from ____
Steps?
6 isoprenoid units
- 2 units used to form geranyl diphosphate
- A third unit is added to form farnesyl diphosphate
- 2 farnesyl diphosphates are used to synthesize squalene
Squalene epoxidase requires _____
___ represents the first sterol produced in the pathway to cholesterol
NADPH and O2
Lanosterol (formed from squalene)
There are ___ steps from lanosterol to cholesterol. The process requires what?
It occurs where?
5
4 NADPH and 3 O2
ER
The steps from lanosterol and cholesterol involve what?
- Removal of methyl group at C14
- Removal of 2 methyl groups at C4
- Reduction of C24 double bond
- Moving 8,9 double bind to 5,6
Other important products produced from the lanosterol to cholesterol pathway
- Prenylated proteins
- Dolichol
- Ubiquinone
Some membrane-associated proteins are prenylated with either ____ or ____ residues, which may anchor the protein to the membrane
Farnesyl or geranylgeranyl
Dolichol is formed from ____ and is required for ____
- Farnesyl diphosphate plus up to 16 more isopentenyl residues
- synthesis of N-linked glycoproteins
Ubiquinone is formed from ____ and is required for ____
- Farnesyl diphosphate plus 3-7 isopentenyl residues
- electron transport chain
ACAT
Acyl CoA cholesterol acyltransferase
*catalyzes lanosterol–>CE
Fates of CE?
Uses?
Either packaged into VLDL or stored in the liver for future use
*they are transported to other tissues for steroid hormone synthesis and vitamin D synthesis
Bile acids are synthesized in the ___ from ___
Liver
Cholesterol
What is the committed step in bile acid synthesis? What does it require?
7 alpha hydroxylase catalyzes rxn from cholesterol to 7 alpha hydroxycholesterol
-requires NADPH, O2, cytochrome P 450, ascorbate (vit C)
The liver receives cholesterol from extrahepatic tissues through ___
LDL receptors and reverse cholesterol transport
The liver secretes cholesterol into the bloodstream via ___
VLDL
3 major regulatory targets in the liver
- HMG-CoA reductase (cholesterol synthesis)
- LDL receptor
- 7alpha-hydroxylase (bile acid synthesis)
Binding of ___ to ____ of the HMG-CoA reductase gene stimulates the transcription of the gene.
___ prevents this
SREBP to the SRE
(Sterol regulatory element-binding protein)
-elevated cholesterol levels in the liver
SREBP interacts with ___, which contains a sterol binding domain, which does what?
ER membrane protein called SCAP (cleavage activating protein)
- when occupied by cholesterol it keeps the SREBP-SCAP complex in the ER
- when cholesterol levels drop, the cholesterol leaves the SCAP sterol binding site
In the ___, SREBP is subjected to proteolysis, and the ___ is released and free to travel to the nucleus Robbins the SRE
Golgi
N-terminal SREBP
When sterol sites of HMG-CoA synthase are occupied by cholesterol it is more susceptible to ___
Proteolysis
Factors which promote phosphorylation of HMG-CoA reductase (causing inhibition)
- Glucagon
- Glucocorticoids
- Cholesterol
Factors which promote dephosphorylation of HMG-CoA reductase (relieving the inhibition)
- Insulin
2. Thyroid hormone
Synthesis of LDL receptors is regulated by ___. The gene is under the same regulatory control as ____
Intracellular cholesterol content
HMG-CoA reductase gene
The destruction caused of LDL receptors is promoted by ____, which is secreted by the ___ and binds to ___
PCSK9 (proprotein convertase subtilisin/kexin 9)
- liver
- the LDL receptor at a site other than the LDL binding site
When the PCSK9-LDL receptor complex is internalized , the presence of PCSK9 targets ___
The complex to the lysosomes (instead of recycling the receptor)
Bile acids bind the ___, which does what?
- FXR (farnesyl X receptor)
- Suppresses the synthesis of 7alpha-hydroxylase (which is the committed step in bile acid synthesis)
Equation for LDL cholesterol
Total cholesterol - [HDL + (triglycerides/5)]
