Statins Flashcards
Mechanism of how we synthesize cholesterol
Meaning of Atherosclerosis?
Describe the process, progressing to advanced plaque and to Atherothrombosis
Athero = Artery tissues. Sclerosis = hardening
Irritant, damage to endothelial layer, Monocyte adhesion and migration into intima layer where they differentiate into macrophages
V. large cells with lipid droplets (foam cells) could die via apoptosis to release lipids and have a large necrotic lipid core.
Smooth muscle cells in the media layer become activated by the inflammation, undergoes differentiation (fibroblast-like). Fibrous cap formed.
If endothelium is denuded - collogen fibres exposed to blood - results in platelet activation and get a Thrombus forming.
What also happens is that foam cells release their signals after they die, inducing smooth muscle into depositing Ca into the plaque. This makes the fibrous cap harder and stiffer.
Loss of elasticity = the fibrous cap can rupture that can lead to platelet activation and thrombosis
Where is Cholesterol synthesized? Where is out found? Colour?
Cholesterol is synthesised in the liver.
It’s found in cell walls of animals and humans.
Isolated cholesterol is a white, flaky solid that is insoluble in aq environments.
3 Biological roles of cholesterol?
- CL
- D
- B
Important component of cell linings.
It helps in the digestion of lipids.
It is a key component in the building of hormones.
What is the lipoprotein?
To act as a carrier vehicle for cholesterol, since cholesterol is a fat soluble so it cannot travel through the bloodstream on it’s own.
The 2 types are:
HDL - good cholesterol
>transferred to bile acids and disposed off.
LDL - bad cholesterol
>blocks blood vessels, especially arteries that feed blood to the heart
What is Hypercholestraemia
High blood cholesterol, usually a result of high LDL/ low HDL.
Leads to atherosclerosis,
decreased blood + O2 supply to heart
heart attack
death
Total cholesterol
<200 mg/dL: normal levels
200 - 239 mg/dL: borderline
>240 mg/dL: risk CHD increased 2fold
Cholesterol biosynthesis (7 steps)
Acetyl-CoA –> HMG CoA –> Mevalonate –> Mevalonate pyrophosphate –> Isopentenyl pyrophosphate –> Farnesyl pyrophosphate –> Squalene synthase –> Cholesterol
Claisen Condensation
Ester (alpha position is deprotonated to form an ester enolate).
Enolate acts as a Nu and attack an ester
Carbonyl reformed
Alpha position deprotonated to form a doubly stabilised enolate
Statins: HMG CoA reductase inhibitors
2 Acetyl CoA (H removed to generate nucleophile) –> Aceoacetyl CoA –> HMG-CoA –> Hydroxymethylglutarate
Show how malvalonate is phosphorylated to form malvalonate pyrophosphate
2ATP - 2ADP –> pyrophosphate
ATP - ADP –> 3-phospho-5-pyrophosphate mevalonate
remove phospho + OH –> dimethylallyl pyrophosphate
Isomerase –> 3isopentyl pyrophosphate
