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DYS: Biology > Therapeutics + biological targets > Flashcards

Therapeutics + biological targets Flashcards

1
Q

What do H2RA inhibit

A

Histamine H2 receptors

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2
Q

What does histamine target

A

The parietal cell by stimulating fusion of intracellular tubulovesicles with the apical membrane. Surface of apical membrane increase as number of proton pumps on apical membrane increase.

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3
Q

What binds to H2 receptors

A

Histamines and H2RA

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4
Q

What are H2 receptors an example of

A

GPCRs

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5
Q

Activation of H2 receptor leads to…

A

Formation of cyclic AMP via G protein mediated signalling

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6
Q

3 amino acids which help histamine bind to H2 receptor

A

Asp-98
Asp-186
Thr-190

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7
Q

Role of Asp-98

A

Form ionic interactions with NH3+ group of histamine

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8
Q

Which 2 amino acids form hydrogen bonds with nitrogen atoims of imidazole ring of histamine

A

Asp-186 + Thr-190

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9
Q

What happens when H2RA binds to H2 receptor

A

It traps receptor in an inactive conformation

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10
Q

Reversible inhibition

A

Fast dissociation of inhibitor

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11
Q

Irreversible inhibition

A

Slow dissociation of inhibitor

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12
Q

How many types of carbonic anhydrase encoded by human genome

A

9

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13
Q

Where is Carbonic anhydrase II

A

In tissues, including eye, stomach, kidney, liver

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14
Q

What is the function of Carbonic anhydrase

A

Required for secretion of HCl by parietal cell.

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15
Q

What disease is treated when inhibiting carbonic anhydrase II

A

Glaucoma (acetazolamide)

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16
Q

What type of protein is CA II + why

A

Metallo-protein due to Zn2+ in active site (spherical protein with a hole)
- Zn2+ ions are held in place three histidine residues.

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17
Q

What holds the Zn2+ in CA II active site

A

Interactions with histidine residues

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18
Q

What do NSAIDs inhibit

A

COX enzymes = involved in the synthesis of prostaglandins

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19
Q

What are the 2 COX enzymes

A

COX-1 + COX-2

- structurally very similar

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20
Q

Why is COX-1 important

A

For renal function and the protection of the epithelial lining in the stomach which is due to the role of prostaglandin signalling in stimulating mucus secretion of mucous cells
- prevalent in many tissues

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21
Q

NSAIDs can lead…

A

Reduced prostaglandin signalling in stomach epithelium results in reduced protection of the gastric surface cells (due to lack of mucus secretion) against gastric acid leading to tissue damage + peptic ulcers

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22
Q

Where are COX-2 protein levels increased

A

Inflamed tissues where prostaglandin have a role in inflammatory signalling

23
Q

Which COX enzyme is responsible for the beneficial effects of NSAIDs

24
Q

Where are COX enzymes

A

Attached to the endoplasmic reticulum membrane

25
COX enzymes responsible for
Synthesis of prostaglandin using arachidonic acid as a substrate
26
Two reactions that COX carry out
Arachidonic acid > Prostaglandin G2 > Prostaglandin H2 COX converts arachidonate to prostaglandin G2 which moves to the second active site where peroxidase reaction converts Prostaglandin G2 to Prostaglandin H2
27
What type of inhibition is NSAID ibuprofen with COX
Reverse inhibition | - prevents simultaneous binding of arachidonate inhibits formation of prostaglandins
28
What type of inhibition is NSAID aspirin with COX
Irreversible inhibition - aspirin alters substrate binding site of enzyme by covalent modification - aspirin transfers an acetyl group to serine (ser-530) near arachidonate binding site - Increased acetylated ser-530 inhibits binding by steric hindrance
29
Interactions of arachidonate with COX
-ively charge carboxylate group of arachidonic acid and the +ively charged amino group of the side chain of amino acid arginine-120
30
Which COX enzyme causes adverse effects
COX-1 - inhibition by NSAIDs lead to reduced prostaglandin signalling in the stomach epithelium causing reduced protection of the gastric surface cells against gastric acid. Leading to tissue damage + peptic ulcers
31
Which COX is present in low amounts
COX-2
32
Where are COX enzymes
Intracellular + attached to the endoplasmic reticulum membrane
33
How many active sites do COX enzymes have
2 | - in close proximity
34
Where do NSAIDs bind to in the COX enzyme
Arachidonate binding site - the -vely charged carboxylate -coo binds to Arg-120 - inhibiting formation of prostaglandins
35
Why is it difficult to produce selective inhibitors
COX-1 + COX-2 are so similar - we only want it to inhibit COX-2 has it has beneficial effects - selective inhibitors are designed to be bulky as the snugly fit into COX-2 but not COX-1 due to steric hindrance
36
Different amino acids lining each COX enzyme active site
``` COX-1 = Isoleucine COX-2 = Valine ```
37
Use of PPIs
prevent further tissue damage by gastric acid and allow tissue repair by reducing gastric acid production
38
Why are PPIs enteric coated
React in acidic environment of the canaliculus - ionised - wont pass
39
What do PPIs bind and inhibit
Gastric Proton Pump (H+,K+ ATPase) | - reacts with cysteine residue of the proton pump
40
What type of transport mechanism does PPI use to enter cell
Passive diffusion through basolateral membrane and then apical membrane.
41
How does gastric proton pump
Exists in 2 main states: E1 (cytoplasmic open) + E2 state (luminal open) - E1 = high affinity to H+ ions; k+ is released into the cytoplasm
42
What does transitioning of the proton pump between states require
ATP hydrolysis - involving phosphroylation of cytoplasmic domain
43
Type of inhibition of PPIs
Irreversible - covalent modification of the proton pump - PPI-CYS adducts inhibit conversion of luminal open E2 to Cytoplasmic open E1 - inhibit via allosteric interactions between transmembrane domain + cytoplasmic enzyme domain
44
What do PPIs form with Cysteine residues
Disulphide bonds
45
Four different CYS residues in transmembrane domain
CYS - 813 (fast recovery; all PPIs) - 822 - 321 - 892
46
What CYS residue can all PPIs inhibit + why is it fast recovery of Acid production
CYS 813 - adducts are unstable so the PPI and disulphide bond between cysteine and PPI is reduced - activity of proton pump is restored leading to fast recovery of acid production
47
Example of PPI that can modify CYS-822
Pantoprazole
48
CYS 822 + its slow recovery of acid
Located deep in the transmembrane domain | - Cysteine residue is more stable + leads to slow recovery of acid production
49
Which PPI does CYS 321 react with + and what type of recovery of acid production
Lansoprazole | Leads to intermediary recovery of acid production
50
How is food/proteins broken down in the absence of gastric acid
Usually it would be activating pepsinogen into pepsin to be broken down for uptake of amino acids in duodenum However with the absence of gastric acid; the proteolytic + degradative enzymes secreted by the pancreas e.g. proteases into the duodenum do just that.
51
Reasons to use a combination 2 antibiotics
Reduce occurrence of antibiotic resistance | More effective than using one antibiotic§
52
What does Zn2+ interact with in carbonic anhydrase
Water - first step = act as electrophile; promotes ionisation of water to form hydroxide - histidine aids in taking the proton - hydroxide ion reacts with CO2 in active site to form bicarbonate HC03-, released with H20.
53
How does CA II inhibitor e.g. acetazolamide inhibit CA II
They bind to carbonic anhydrase which inhibits the catalysation of water and carbon dioxide to bicarbonate ions + proton (hydroxide ion)
54
What example of inhibition is acetazolamide
Competitive or reversible

DYS: Biology (4 decks)

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