Statins Flashcards
what is cholesterols role in the body?
-important in biosynthesis and cell membrane structure
what are used to transport cholesterol around the blood supply?
Low-density and high-density lipoproteins
where do LDLs carry cholesterol to?
cells
where do HDLs carry cholesterol from and to?
from cells to the liver
what four things can happen if fatty plaques form in arteries due to cholesterol?
- artherosclerosis,
- clot formation,
- stroke and
- heart attack
Explain how cholesterol is converted to bile acids and bile salts and what happens after??
- 7α-hydroxylase catalyses initial rate-limiting step of the conversion.
- then the bile acids are mostly reabsorbed through the enterohepatic circulation and returned back to the liver
- this exerts a negative feedback control on 7α-hydroxylase
Explain the process of cholesterol biosynthesis and state the number of steps between each reaction.
- Acetyl CoA (2 steps to 2)
- HMG CoA (using its reductase enzyme)
- Mevalonic acid (3 steps to 4)
- Isopentenyl Pyrophosphate (3 steps to 5)
- Farnesyl pyrophosphate (2 steps to 6)
- Squalene (2 steps to 7)
- Lanosterol (20 steps to 8)
- Cholesterol
where is the primary control site for cholesterol biosynthesis?
HMG-CoA to Mevalonic Acid via the use of HMG CoA reductase enzymes
where does statin target to reduce cholesterol levels?
HMG-CoA reductase enzymes - the enzyme catalysing the rate limiting step in cholesterol synthesis.
what are the roles of Glutamic acid - 599 and Histidine - 866 in the reduction of HMG-CoA by HMG-CoA reductase?
act as acid catalysts
what is the role of Lysine - 691 in the reduction of HMG-CoA by HMG-CoA reductase?
stabilises the negatively charged oxygen of Mevaldyl-CoA and the transition state leading to it. So it lowers activation energy for first step
what is the role of aspartate residues - 767 in the reduction of HMG-CoA by HMG-CoA reductase?
stabilises Glu-599 and Lys 691
How does the HMG-CoA reductase inhibitor work - competitive or non-competitive?
by competitive inhibition of the reductase enzyme
it has a higher affinity for the enzyme than the substrate HMG-CoA
what is the general structure of Type 1 statins?
- polar head
- hydrophobic moiety
- lots of asymmetric centres
- with a decalin ring
e. g. Lovastatin, Simvastatin
what is the benefit of making Lovastatin analogues with a longer interaction with the enzyme?
- usually, an increase in the amount of HMG-CoA would reduce the effectiveness of the drug
- but with the analogue, the enzyme and drug will be bound for longer therefore reducing effects of an increase in HMG-CoA concentrations
what structural modifications can be made to lovastatin to create a longer binding time with the enzyme?
- Make Ether side-chain analogues
- Homologation of the lactone ring
- converting lovastatin to
mevalonate analogue (changing stereochemistry at the hydroxy-bearing-carbon in the lactone
what is the purpose of the homologation of the lactone ring?
to develop a lactone homologue that is compatible with the complex and has the same sensitive structural features of lovastatin.
Explain how Lovastatin is converted to Mevalonate and the consequence of this change?
- Mevalonate has a hydrody-bearing carbon just like HMG-CoA (the substrate). But lovastatin doesn’t.
- however, the consequence of this change hasn’t been identified yet (so no results yet)
what is the consequence of changing the ester analogue of lovastatin to an ether analogue?
- showed that the absence of the carbonyl (C=O) had a detrimental effect on the inhibitory strength
- concludes that side-chain ethers are weaker inhibitors than their corresponding ester analogues
what are some downsides to Type 1 statins?
- Various side effects e.g. constipation, flatulence, dyspepsia, myopathy
- difficult to synthesise (main source is from mould cultures)- so it is semi-synthetic
- Large number of asymmetric centres
what are type 2 statins made up of?
synthetic agents
what is the general structure of type 2 statins?
- Larger hydrophobic moiety
- no asymmetric centres
- structures with similar features
e. g. fluvostatin, atorvastatin, rosuvastatin, cerivastatin
which is the most potent type 2 statin and why?
rosuvastatin due to the sulphonamide group
which is the most hydrophobic type 2 statin?
cerivastatin
which is the least hydrophobic type 2 statin?
rosuvastatin
where do statins with low hydrophobic character target?
liver cells
which have more side effects, lower or higher hydrophobic statins? hence why type of statins are these?
higher hydrophobic statins (aka type 2 statins)
which cells have transport proteins for statins?
Liver cells
where does the majority of cholesterol synthesis take place?
in liver cells
what is thought to be the main cause of side effects from the use of statins?
inhibition of HMGR in other cells such as muscle cells
why was cerivastatin withdrawn from the market?
cause it caused rhabdomyolysis in patients (severe muscle toxicity which can be fatal)
which part of the statin molecule mimics the HMGR substrate?
the polar head
with the hydrophobic part forming more binding interactions
which type of statins can cross cell membranes easier?
Type 2 statins
what intermediate are statins closer mimics of?
the first reaction intermediate (Mevaldyl CoA)
why are statins also called transition-state analogues?
because they bear a resemblance to the transition state for the first stage of the reaction mechanism.
what is the binding site of type 2 and type 1 statins?
type 2 = methylethyl substituent
type 1 = decalin ring
why is rosuvastatin the most potent statin?
- forms additional H-bonds
- Sulfone oxygen forms a hydrogen bonding interaction with Ser-565
- Sulfone group also interacts uniquely with Arg-568
what helps rosuvastatin select the HMG-CoA Reductase?
the sulfone group
what is part of the HMGRI is useful for inhibition?
3,5-dihydroxycarboxylate
what effect does altering the two carbon distance between C5 and the ring system have?
diminishes or
fails to improve activity
what is the decalin ring essential for in Ring A subclass statins?
The decalin ring is essential for anchoring the compound to the enzyme active site
what effect does a methyl substitution at R2 position have in Ring A subclass statins?
Methyl substitution at the R2 position increases activity
what effect does a b-Hydroxyl group have on the Ring A subclass statin?
b-Hydroxyl group substitution at the R1 position of the statin enhances hydrophilicity and
may provide some cellular specificity.
what effect does substituting a aryl group, hydrocarbon chain, amide or sulphonamide into the Ring B subclass structure have on the statin?
enhances lipophilicity and inhibitory activity.
