Statins

Question 1

what is cholesterols role in the body?

Answer 1

-important in biosynthesis and cell membrane structure

Question 2

what are used to transport cholesterol around the blood supply?

Answer 2

Low-density and high-density lipoproteins

Question 3

where do LDLs carry cholesterol to?

Answer 3

cells

Question 4

where do HDLs carry cholesterol from and to?

Answer 4

from cells to the liver

Question 5

what four things can happen if fatty plaques form in arteries due to cholesterol?

Answer 5

1. artherosclerosis,
2. clot formation,
3. stroke and
4. heart attack

Question 6

Explain how cholesterol is converted to bile acids and bile salts and what happens after??

Answer 6

• 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

Question 7

Explain the process of cholesterol biosynthesis and state the number of steps between each reaction.

Answer 7

1. Acetyl CoA (2 steps to 2)
2. HMG CoA (using its reductase enzyme)
3. Mevalonic acid (3 steps to 4)
4. Isopentenyl Pyrophosphate (3 steps to 5)
5. Farnesyl pyrophosphate (2 steps to 6)
6. Squalene (2 steps to 7)
7. Lanosterol (20 steps to 8)
8. Cholesterol

Question 8

where is the primary control site for cholesterol biosynthesis?

Answer 8

HMG-CoA to Mevalonic Acid via the use of HMG CoA reductase enzymes

Question 9

where does statin target to reduce cholesterol levels?

Answer 9

HMG-CoA reductase enzymes - the enzyme catalysing the rate limiting step in cholesterol synthesis.

Question 10

what are the roles of Glutamic acid - 599 and Histidine - 866 in the reduction of HMG-CoA by HMG-CoA reductase?

Answer 10

act as acid catalysts

Question 11

what is the role of Lysine - 691 in the reduction of HMG-CoA by HMG-CoA reductase?

Answer 11

stabilises the negatively charged oxygen of Mevaldyl-CoA and the transition state leading to it. So it lowers activation energy for first step

Question 12

what is the role of aspartate residues - 767 in the reduction of HMG-CoA by HMG-CoA reductase?

Answer 12

stabilises Glu-599 and Lys 691

Question 13

How does the HMG-CoA reductase inhibitor work - competitive or non-competitive?

Answer 13

by competitive inhibition of the reductase enzyme

it has a higher affinity for the enzyme than the substrate HMG-CoA

Question 14

what is the general structure of Type 1 statins?

Answer 14

• polar head
• hydrophobic moiety
• lots of asymmetric centres
• with a decalin ring
  e. g. Lovastatin, Simvastatin

Question 15

what is the benefit of making Lovastatin analogues with a longer interaction with the enzyme?

Answer 15

• 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

Question 16

what structural modifications can be made to lovastatin to create a longer binding time with the enzyme?

Answer 16

1. Make Ether side-chain analogues
2. Homologation of the lactone ring
3. converting lovastatin to
   mevalonate analogue (changing stereochemistry at the hydroxy-bearing-carbon in the lactone

Question 17

what is the purpose of the homologation of the lactone ring?

Answer 17

to develop a lactone homologue that is compatible with the complex and has the same sensitive structural features of lovastatin.

Question 18

Explain how Lovastatin is converted to Mevalonate and the consequence of this change?

Answer 18

• 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)

Question 19

what is the consequence of changing the ester analogue of lovastatin to an ether analogue?

Answer 19

• 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

Question 20

what are some downsides to Type 1 statins?

Answer 20

1. Various side effects e.g. constipation, flatulence, dyspepsia, myopathy
2. difficult to synthesise (main source is from mould cultures)- so it is semi-synthetic
3. Large number of asymmetric centres

Question 21

what are type 2 statins made up of?

Answer 21

synthetic agents

Question 22

what is the general structure of type 2 statins?

Answer 22

• Larger hydrophobic moiety
• no asymmetric centres
• structures with similar features
  e. g. fluvostatin, atorvastatin, rosuvastatin, cerivastatin

Question 23

which is the most potent type 2 statin and why?

Answer 23

rosuvastatin due to the sulphonamide group

Question 24

which is the most hydrophobic type 2 statin?

Answer 24

cerivastatin

Question 25

which is the least hydrophobic type 2 statin?

Answer 25

rosuvastatin

Question 26

where do statins with low hydrophobic character target?

Answer 26

liver cells

Question 27

which have more side effects, lower or higher hydrophobic statins? hence why type of statins are these?

Answer 27

higher hydrophobic statins (aka type 2 statins)

Question 28

which cells have transport proteins for statins?

Answer 28

Liver cells

Question 29

where does the majority of cholesterol synthesis take place?

Answer 29

in liver cells

Question 30

what is thought to be the main cause of side effects from the use of statins?

Answer 30

inhibition of HMGR in other cells such as muscle cells

Question 31

why was cerivastatin withdrawn from the market?

Answer 31

cause it caused rhabdomyolysis in patients (severe muscle toxicity which can be fatal)

Question 32

which part of the statin molecule mimics the HMGR substrate?

Answer 32

the polar head | with the hydrophobic part forming more binding interactions

Question 33

which type of statins can cross cell membranes easier?

Answer 33

Type 2 statins

Question 34

what intermediate are statins closer mimics of?

Answer 34

the first reaction intermediate (Mevaldyl CoA)

Question 35

why are statins also called transition-state analogues?

Answer 35

because they bear a resemblance to the transition state for the first stage of the reaction mechanism.

Question 36

what is the binding site of type 2 and type 1 statins?

Answer 36

type 2 = methylethyl substituent | type 1 = decalin ring

Question 37

why is rosuvastatin the most potent statin?

Answer 37

- forms additional H-bonds - Sulfone oxygen forms a hydrogen bonding interaction with Ser-565 - Sulfone group also interacts uniquely with Arg-568

Question 38

what helps rosuvastatin select the HMG-CoA Reductase?

Answer 38

the sulfone group

Question 39

what is part of the HMGRI is useful for inhibition?

Answer 39

3,5-dihydroxycarboxylate

Question 40

what effect does altering the two carbon distance between C5 and the ring system have?

Answer 40

diminishes or | fails to improve activity

Question 41

what is the decalin ring essential for in Ring A subclass statins?

Answer 41

The decalin ring is essential for anchoring the compound to the enzyme active site

Question 42

what effect does a methyl substitution at R2 position have in Ring A subclass statins?

Answer 42

Methyl substitution at the R2 position increases activity

Question 43

what effect does a b-Hydroxyl group have on the Ring A subclass statin?

Answer 43

b-Hydroxyl group substitution at the R1 position of the statin enhances hydrophilicity and may provide some cellular specificity.

Question 44

what effect does substituting a aryl group, hydrocarbon chain, amide or sulphonamide into the Ring B subclass structure have on the statin?

Answer 44

enhances lipophilicity and inhibitory activity.