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LIFE207 > Phase 3 Reactions > Flashcards

Phase 3 Reactions Flashcards

1
Q

What are Phase 2 reactions usually catalysed by?

A

Transferase enzymes

Transferring a polar group from a donor or conjugating agent to the phase 1 metabolite

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2
Q

What enzyme catalyses glucuronidation?

A

Glucuronosyltransferase

UDP - glucuronyltransferase (UGT)

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3
Q

What enzyme catalyses sulphation?

A

Sulphotransferase

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4
Q

What enzyme catalyses amino acid conjugation?

A

N-acyl transferase

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5
Q

What enzyme catalyses Acetylation?

A

N-Acetyltransferase

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6
Q

What enzyme catalyses methylation?

A

Methyltransferase

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7
Q

What enzyme catalyses glutathione conjugation?

A

Glutathione S-transferase

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8
Q

What is glutathione conjugation important?

A

Important for detoxification

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9
Q

Where is UGT found?

A

Liver, intestine, kidneys, brain, adrenal glands, spleen and thymus

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10
Q

What is the donor molecule for glucuronidation? Why?

A

UDPGA - Uridine Diphosphate Glucuronic Acid

High energy
Abundant

Also related to glycogen synthesis - endogenous

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11
Q

What organelle is UGT found in?

A

Smooth endoplasmic recticulum

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12
Q

What does UGT do?

A

Transfers Glucuronyl group from UDPGA to nucleophilic O, N or S

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13
Q

What’re the similarities and differences between UGT1 UGT2 and UGT3?

A

All 3 proteins contain similar region which recognises UDP glucuronic acid

Each proteins has a different region for substrate recognition

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14
Q

Which 2 UGT enzymes are the key subtypes involved in drug glucuronidation?

A

UGT1 and UGT2

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15
Q

Give an example of O-glucuronidation.

A

Salicylic acid

Both -COOH and -OH groups can undergo glucuronidation (can be doubly conjugated)

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16
Q

Give an example of N-glucuronidation.

A

Sulphanilamide

UDPGA coordinates with both NH2 groups, this is recognised by UGT

Both sites are then glucuronidated

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17
Q

What is the donor molecule for sulphation? Why?

A

PAPS - 3’-phosphoadenosine-5’-phosphosulfate

Energy rich

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18
Q

What is the cytosolic transferase responsible for sulphation?

A

Sulphotransferase

19
Q

What predominates at low substrate concentration, sulphation or glucuronidation? Why?

A

Sulphation

Because there is relatively less PAPS in cell cytosol compared to UDPGA

20
Q

What predominates at high substrate concentration, sulphation or glucuronidation? Why?

A

Glucuronidation

Because there is relatively less PAPS in cell cytosol compared to UDPGA

21
Q

Give an example of sulphation that stops Phase 1 metabolism.

A

Paracetamol

-OH is sulphonated which stops Phase 1 metabolism

It is then excreted, build up causes toxicity issues

22
Q

Where does glycine conjugation occur?

A

In the mitochondria

23
Q

What is the donor molecule for glycine conjugation?

A

Glycine (glutamine, taurine)

No HIGH ENERGY donor molecule

Activated to form Acyl CoA intermediate

24
Q

How does a drug become activated prior to glycine conjugation?

A

-COOH reacts with ATP to form C(O)-AMP

-C(O)-AMP reacts with Coenzyme-A synthetase to form -C(O)-S-CoA

Then reacts with glycine via acyl Coenzyme-A thioester intermediate

25
Q

What enzyme catalyses glycine conjugation?

A

N-Acyl transferase

26
Q

Why is glutathione conjugation important?

A

As it attacks epoxides and quinoneimines

These are reactive metabolites

27
Q

What enzyme catalyses glutathione conjugation?

A

Glutathione S-transferase - GST

28
Q

What is the high energy donor for glutathione conjugation and where is GST found?

A

Found in the cytosol of hepatocytes

No high energy donor as substrates are already chemically reactive

29
Q

What can glutathione conjugated metabolites undergo further metabolism to?

A

Further metabolism to mercapturic acids

30
Q

Give an example of a quinoneimine being produced from Phase 1 metabolism

A

Paracetamol is oxidised by CYP450 enzyme to form N-acetyl-p-benzoquinoneimine (NAPQI) which is very reactive and hence bad

It then undergoes glutathione conjugation to make it more hydrophilic and can then be excreted

31
Q

What is often referred to as Phase 3 metabolism of drugs?

A

Mercapturic acid synthesis

It is an inter-organ pathway involving the liver and kidneys

32
Q

When does Phase 3 metabolism occur?

A

ONLY after glutathione conjugation reactions done in Phase 2

33
Q

What’s the predominant reaction for primary amines and sulphonamides?

A

Acetylation and sulphation

34
Q

What is the high energy donor for acetylation?

A

Acetyl Coenzyme-A

35
Q

What can happen as a result of acetylation?

A

Acetylation often decreases water solubility and hence it can precipitate out in the kidneys leading to renal toxicity

36
Q

What are commonly methylated functional groups?

A

Phenols
Catechols
Amines
N=heterocycles
sulfhydryls

37
Q

What does methylation require the presence of?

A

Cofactor - a methyl donor

S-adenosyl methionine (SAM)

38
Q

What 2 specific enzymes catalyse methylation?

A

Catechol-O-methyltransferase - COMT
- O-methylation

Thiopurine S-methyltransferase - TPMT
- S-methylation

39
Q

How is 6-mercaptopurine metabolised for excretion?

A

Metabolised to methyl 6-mercaptopurine in the presence of TPMT and SAM

40
Q

How does 6-mercaptopurine become pharmaceutically active?

A

It is oxidised twice by xanthine oxidase to 6-thiouric acid

This is cytotoxic and kills cancer cells

41
Q

Give an example of a methylation reaction COMT catalyses.

A

L-DOPA, both -OHs can be methylated

In the presence of SAM ofc

42
Q

What metabolism pathways commonly occur to -OH?

A

Glucuronidation
Sulphation
Methylation

43
Q

What metabolic pathways commonly occur to -COOH?

A

Glucuronidation
Glycine conjugation

44
Q

What metabolic pathways commonly occur to -NH2?

A

Acetylation
Glucuronidation
Sulphation

LIFE207 (9 decks)

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