Hardcastle case study 1 Flashcards
(20 cards)
Why is cholesterol needed
It is an essential cell component particularly in the cell membrane
Precursor to steroid hormones
What are high cholesterol levels linked to
- angina
- heart attack
- stroke
- cardiovascular diseases
What are the two different types of cholesterol which circulate in the blood
High density lipoproteins - hard cholesterol molecules sometimes known as good cholesterol
Low density lipoproteins - also known as bad cholesterol
What is the problem with low density lipoproteins (bad cholesterol)
The low density lipoproteins can form a coating/plaque on the inside of blood vessels. This plaque can narrow blood vessels which causes angina as the heart does not get enough blood. Part of plaque can also shed of into the blood stream causing a clot. These clots lead to heart attacks or strokes
Where does cholesterol come from
We can get cholesterol from our diet or it can be biosynthesised in the body via the mevalonate
describe the mevalonate pathway
Two acetyl CoA molecules are condensed together to produce acetoacetyl CoA catalysed by thiolase enzyme. We then add another acetal group to produce HMG-CoA using HMG-CoA synthase. We then reduce HMG-CoA using HMG-CoA reductase to mevalonate. The mevalonate then gets phosphorolayted by a variety of kinases. Then undergoes many other enzyme reactions to produce dimethylallyl pyrophosphate
What is the basic building block of all steroids
Squalene
How do we produce squalene
Squalene can be produced by joining the 3-isopentenyl pyrophosphate and the dimethylallyl pyrophosphate using squalene synthase
How do we synthesise cholesterol from squalene
Squalene is converted to squalene epoxide using squalene monooxygenase. This squalene epoxide can then be converted into lanosterol using squalene epoxidase. This lanosterol undergoes a variety of enzyme reactions to produce cholesterol
What is the chosen target for the cholesterol lowering drug
The HMG-CoA reductase step from HMG-CoA to mevalonate is the rate determining step for the whole system. So if we target this step we target the whole of the cholesterol biosynthesis.
What are statins
Inhibitor of HMG-CoA reductase
What is the mechanism of action for a natural statin/HMG
Natural statins are typically prodrugs. Natural statins contain a hydroxylactone ring liver enzymes hydrolyze the lactone ring to form the active dihydroxy acid groups.
Dihydroxy acid groups structurally similar to HMG-CoA. The statins therefore compete with HMG-CoA. Statins act as competitive inhibitors
What doe HMG-CoA reductase do
Converts HMG-CoA into mevalonate
Where do natural stains come from
These were discovered from microbial fermentation of fungi or molds and served as the blueprint for later drug development.
Give examples of natural statins
Mevastatin and lovastatin
What is simvastatin
A semi-synthetic derivative which is 2.5 times more potent
What are synthetic statins
Inspired by the natural statin scaffold but with structural modifications. developed to improve potency, bioavailabity and safety
Give examples of synthetic statins
Fluvistatin
Cerivastatin
Rosuvastatin
Atorvastatin
describe the action of synthetic statins
synthetic statins contain a dihydroxy acid group that closely resembles HMG-CoA, this interacts with the polar active site (cis-loop) of HMG-CoA reductase. Synthetic statins often have bulky, hydrophobic side chains. These side chains induce a conformational change in the enzyme creating a hydrophobic pocket near the active site. By reshaping the enzyme to fit better around the drug, they form stronger binding interactions, particularly with two alpha helices (Lα1 and Lα10). This leads to very high potency.
