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DYS: Biology > Therapeutics + biological targets > Flashcards

Therapeutics + biological targets Flashcards

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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

A

COX-2

24
Q

Where are COX enzymes

A

Attached to the endoplasmic reticulum membrane

25
Q

COX enzymes responsible for

A

Synthesis of prostaglandin using arachidonic acid as a substrate

26
Q

Two reactions that COX carry out

A

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
Q

What type of inhibition is NSAID ibuprofen with COX

A

Reverse inhibition

- prevents simultaneous binding of arachidonate inhibits formation of prostaglandins

28
Q

What type of inhibition is NSAID aspirin with COX

A

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
Q

Interactions of arachidonate with COX

A

-ively charge carboxylate group of arachidonic acid and the +ively charged amino group of the side chain of amino acid arginine-120

30
Q

Which COX enzyme causes adverse effects

A

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
Q

Which COX is present in low amounts

A

COX-2

32
Q

Where are COX enzymes

A

Intracellular + attached to the endoplasmic reticulum membrane

33
Q

How many active sites do COX enzymes have

A

2

- in close proximity

34
Q

Where do NSAIDs bind to in the COX enzyme

A

Arachidonate binding site

  • the -vely charged carboxylate -coo binds to Arg-120
  • inhibiting formation of prostaglandins
35
Q

Why is it difficult to produce selective inhibitors

A

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
Q

Different amino acids lining each COX enzyme active site

A 
COX-1 = Isoleucine
COX-2 = Valine
37
Q

Use of PPIs

A

prevent further tissue damage by gastric acid and allow tissue repair by reducing gastric acid production

38
Q

Why are PPIs enteric coated

A

React in acidic environment of the canaliculus - ionised - wont pass

39
Q

What do PPIs bind and inhibit

A

Gastric Proton Pump (H+,K+ ATPase)

- reacts with cysteine residue of the proton pump

40
Q

What type of transport mechanism does PPI use to enter cell

A

Passive diffusion through basolateral membrane and then apical membrane.

41
Q

How does gastric proton pump

A

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
Q

What does transitioning of the proton pump between states require

A

ATP hydrolysis - involving phosphroylation of cytoplasmic domain

43
Q

Type of inhibition of PPIs

A

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
Q

What do PPIs form with Cysteine residues

A

Disulphide bonds

45
Q

Four different CYS residues in transmembrane domain

A

CYS

  • 813 (fast recovery; all PPIs)
  • 822
  • 321
  • 892
46
Q

What CYS residue can all PPIs inhibit + why is it fast recovery of Acid production

A

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
Q

Example of PPI that can modify CYS-822

A

Pantoprazole

48
Q

CYS 822 + its slow recovery of acid

A

Located deep in the transmembrane domain

- Cysteine residue is more stable + leads to slow recovery of acid production

49
Q

Which PPI does CYS 321 react with + and what type of recovery of acid production

A

Lansoprazole

Leads to intermediary recovery of acid production

50
Q

How is food/proteins broken down in the absence of gastric acid

A

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
Q

Reasons to use a combination 2 antibiotics

A

Reduce occurrence of antibiotic resistance

More effective than using one antibiotic§

52
Q

What does Zn2+ interact with in carbonic anhydrase

A

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
Q

How does CA II inhibitor e.g. acetazolamide inhibit CA II

A

They bind to carbonic anhydrase which inhibits the catalysation of water and carbon dioxide to bicarbonate ions + proton (hydroxide ion)

54
Q

What example of inhibition is acetazolamide

A

Competitive or reversible

DYS: Biology (4 decks)

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