17. Cholesterol metabolism Flashcards
What is the first committed step of cholesterol synthesis? What does this reaction involve and what enzyme is it catalysed by? Any electron carriers / acceptors involved?
β-Hydroxy β-methylglutaryl-CoA (HMG-COA) → Mevalonate
- Catalysed by HMG-CoA reductase
- This reaction involves removing the CoA group and reducing carbonyl (C=O) into alcohol (C-OH)
- Electron donor, NADPH, provides the reducing power
After mevalonate (6C) is formed, it undergoes 3 step reactions to form ___, which are 5C units that is needed for the synthesis of squalene (30C).
Give the name of the compound, not the name of the functional group
Isoprenyl pyrophosphate
Functional group : isoprene
State the 3 steps involved in converting mavalonate (6C) into isoprenyl pyrophosphate (5C). State if any ATP is consumed
- Mavalonate → phosphomavalonate ; consumption of ATP → ADP (addition of phopshate)
- Phosphomevalonate → 5-pyrophosphomevalonate ; consumption of ATP → ADP (addition of another phosphate)
- 5-pyrophosphomevalonate (6C) → isopentynyl phosphate (5C) ;; consumption of ATP → ADP
In the last step, 5-pyrophosphomevalonate (6C) → isoprenyl phosphate (5C). What is occuring during this step, and why is ATP needed?
Elimination to form C=C (& decarboxylation)
- ATP is needed to generate a phosphate group, which replaces -OH group on C3 (better leaving group).
- Subsequently, C1 is decarboxylated, forming a C=C bond between C2 and C3 (C1 and C2 of isoprenyl phosphate (5C))
Name the 2 types of isoprene units needed for synthesis of squalene (30C). How many of each isoprene units are needed?
Isoprenyl pyrophosphate (4x)
Dimethylallyl pyrophosphate (2x)
30 C squalene = condensation of 15C + 15C. Each 15 C is made from condensation of 2 isoprenyl pyrophosphate and 1 dimethylallyl pyrophosphate
What reaction does isoprenyl pyrophosphate undergo to form dimethylallyl pyrophosphate, and what class of enzyme catalyses this reaction?
Isomerisation of C=C bond ;; catalysed by isomerase
- Between C1 and C2 → between C2 and C3
After squalene (30C) is produced, how does it form cholesterol?
It undergoes cyclisation via 21 enzymatic steps.
After cholesterol is synthesised, what reaction does it undergo before it is packaged into VLDL? What enzyme catalyses this reaction?
Cholesterol has an alcohol group
It undergoes esterification : Cholesterol + fatty acyl CoA → cholesteryl ester (Acyl-CoA cholesterol)
- Catalysed by ACAT ; acyl-CoA cholesterol acyl transferase
What are the 2 main categories of regulatory strategies (control) in regulating cholesterol homeostasis?
- Short term control
- Long term control
What is the primary regulatory strategy for controlling cellular cholesterol levels?
Long term control via controlling amount of HMG reductase.
What does short term control of cholesterol involve, and how is it regulated? [3]
Short term control of cholesterol involves regulating the enzymatic activity of HMG-CoA reductase. HMG-CoA reductase is regulated by
1. Competitive inhibition
2. Allosteric effects
3. Covalent modification → reversible phosphorylation
HMG-CoA reductase : enzyme involved in the first committed step of cholesterol synthesis
Short term control
Explain how a low ATP/AMP ratio inhibits cholesterol synthesis through covalent modification of HMG-CoA reductase
- A low ATP/AMP ratio signifies that the body is low in energy, thus this activates AMP-dependent kinases.
- AMP-dependent kinases phosphorylate HMG-CoA, thus lowering the activity of HMG-CoA
- Therefore cholesterol synthesis, a process which consumes ATP, is inihibited. Thus this conserves energy.
Long term control
Cholesterol synthesis can also occur via long term control. What does long term control involve? [2]
- Regulating the amount of enzyme (HMG-CoA reductase)
- Regulating the expression / amount of LDL receptors
How is the amount of HMG-CoA reductase and amount of LDL receptors controlled?
They are controlled via gene expression via the Sterol Regulatory Element (SRE)
- Amount of protein expressed is controlled on gene level (affects transcription process of mRNA → protein)
What is the SREBP (Sterol regulatory element binding protein) and what does it do?
The SREBP is a transcription factor which binds to SRE in genes for HMG-reductase / LDL receptors, thus increasing transcription and increasing amount of HMG-reductase / LDL receptors ;; thus increasing intracellular cholesterol levels
In order for transcription of HMG-CoA reductase to occur, the SREBP (Sterol regulatory element binding protein) must…?
Must be cleaved off the ER and travel into the nucleus.
Explain how intracellular cholesterol levels are controlled via gene expression when intracellular cholesterol levels in the ER lumen decrease
Key words : SRE (Sterol regulatory element), SREBP, SCAP (SREBP cleavage activating protein)
When intracellular levels in lumen of ER decreases:
- SREBP, a transcription factor with a sterol sensing domain, senses the amount of intracellular cholesterol levels.
- The SCAP changes conformation, and SCAP/SREBP complex travels from ER to Golgi apparatus
- In the golgi apparatus, 2 proteases release the bHLH (transcription factor) of the SREBP.
- bHLH (SREBP) travels into nucleus and binds to SRE present in the promoter region of gene that encode for HMG-CoA reductase
- Activate transcription of HMG-CoA reductase = increase in amount of HMG-CoA reductase = increased cholesterol synthesis ++ increase LDL receptor expression = more LDL and dietary cholesterol enter
- Negative feedback loop : when intracellular cholesterol levels rise again, cholesterol inhibits release of SREBP, inhibiting transcription of enzyme in nucleus.
Meabolic diseases
How does atherosclerosis arise?
Artherosclerosis = buildup of material on artery walls
- When epithelial cells of arteries becomes damaged, high levels of LDL circulating in bloodstream deposit on the cell surface of arteries.
- This attracts WBC (macrophages), and WBC + LDL form foam cells
- However, WBc is unable to engulf the LDL. Thus, this forms a plaque, which narrows the arteries and reducing blood flow through the arteries
Metabolic diseases
Atherosclerosis is a high risk factor for cardiovascular diseases. Explain how atherosclerosis leads to heart attacks / stroke (cardiovascular diseases)
When the plague on the epithelial cells rupture, it leads to blood clotting. Blood clots block the flow of blood through the blood vessels.
- Stoppage of blood flow in heart causes heart attack
- Stoppage of blood flow in brain causes stroke
Metabolic diseases
Explain how Familial hypercholesterolemia could pose a high risk of cardiovascular diseases.
- in Familial hypercholesterolemia, LDL receptors are not expressed / poorly expressed / does not bind to LDL.
- lead to low intracellular levels of cholesterol as cells cannot uptake LDL
- high levels of LDL in bloodstream → deposit in blood vessel → increased risk of artherosclerosis and cardiovascular disease
Familial hypercholesterolemia : linked with LDL
Metabolic diseases
Explain how Tangier disease could pose a high risk of cardiovascular diseases.
- in tangier disease, intracellular cholesterol cannot be packaged into HDL for transport back to liver
- accumulation of cholesterol in cells = lower expression of LDL receptors to stop uptake of cholesterol into cells
- higher levels of LDL in bloodstream
Tangier disease : linked with HDL
What drug can be used to lower cholesterol levels?
Just give the name
Statins
Explain the mode of action of statins on reducing cholesterol levels ;; both in the short term and long term
- Statins act as competitive inhibitors of substrates (HMG-CoA), as they have similar HMG-like groups
- The bulky hydrophobic groups of statins trggers conformation change of HMG-CoA reductase.
- Thus, intracellular cholesterol levels decrease. This causes more LDL receptors to be expressed (SREBP), thus lowering LDL in the bloodstream as more LDL is uptaken by cells.
