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Med Chem Final > Phase 2 Metabolism > Flashcards

Phase 2 Metabolism Flashcards

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1
Q

phase 2 reactions are also known as ____ reactions

A

conjugation reactions

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2
Q

what is the most dominant conjugation pathway?
why?

A

glucuronic acid conjugation (glucuronidation)

this is because it uses glucose which is extremely abundant, and it has broad substrate specificity

glucuronic acid is very water soluble and would make all conjugates sufficiently water soluble for elimination

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3
Q

what is the starting material for glucuronidation?

A

alpha Glucose-1-Phosphate

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4
Q

the starting material for glucuronic acid conjugation is alpha glucose-1-phosphate.

what does this react with?
what does it produce?

A

a-G-1-P reacts with UTP (uridine triphosphate) to produce UDPG (urine diphosphate glucose) + PP (pyrophosphate)

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5
Q

true or false

activated carbon can often serve as a polar functional group to undergo glucuronidation

A

true

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6
Q

give the entire formula for the glucuronic acid conjugation pathway

A

a-G-1-P + UTP -> UDPG + PP

UDPG + 2NAD -> UDPGA + 2NADH (UDPG dehydrogenase)

UDPGA + ROH (substrate) -> B glucuronic acid + UDP (UDP glucuronyl transferase)

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7
Q

what is the conjugating enzyme in glucuronidation

A

UDP glucuronyl transferase

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8
Q

what is the linkage of UDPGA?
is this always the case?

A

ALWAYS alpha linkage

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9
Q

pointing ___ is alpha and pointing ___ is beta

A

down = alpha
up = beta

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10
Q

what is the activated conjugating group in glucuronidation?
what does it do?

A

UDPGA (uridine diphosphate glucuronic acid)

reacts with substrate. has substrate as part of its structure

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11
Q

____ is connected to ____ via alpha linkage

what molecule is this?

A

glucuronic acid is connected to diphosphate via alpha linkage

this is the activated conjugating group (UDPGA)

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12
Q

what enzyme produces UDPGA?

A

UDPG dehydrogenase

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13
Q

does the substrate attack UDPGA or vice versa? explain

A

substrate attacks UDPGA

ALWAYS FROM THE TOP TO GIVE BETA LINKAGE EVERY TIME

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14
Q

What cofactor is used in glucuronidation?
what is it used to for?

A

2NAD are used to oxidize glucose. UDPG -> UDPGA via UDPG dehydrogenase

2NAD reduced to 2NADH

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15
Q

what is the activated conjugating group in sulfation?

A

PAPS

activated sulfate.
3’-phosphoadenosine 5’-phospho sulfate

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16
Q

given the substrate as “ROH”,
what happens to it after sulfation?

A

becomes ROSO3

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17
Q

what supplies sulfate in sulfation?

A

PAPS

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18
Q

explain the substrate specificity of sulfation

A

typical substrate is phenol.
very narrow specificity

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19
Q

explain WHY the specificity of sulfation is very limited

A

for glucuronidation, glucose is constantly being supplied through carbs in our diet

however, sulfate isn’t usually stored in the body

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20
Q

explain in detail how PAPS is formed

A

inorganic sulfate (SO42-) combines with ATP to form APS (adenosine-5’-phosphosulfate) and PP (pyrophosphate). catalyzed by ATP-Sulfate Adenyl Transferase

APS combines with another ATP to form PAPS + ADP.
catalyzed by ATP Kinase

full reaction = 2ATP + SO42- ->
PAPS + ADP + PP

21
Q

what does ATP kinase do in the phase 2 metabolic reactions?

A

in sulfation, ATP kinase adds phosphorus to the 3’ position of APS to form PAPS

22
Q

give an example of amino acid conjugation

A

glutamine conjugation

23
Q

in glutamine conjugation, what is used as the conjugating molecule?

A

glutamine

24
Q

what can you say about the substrate specificity for amino acid conjugation?

A

rather limited.
limited to mainly aryl carboxylic acids and alkyl carboxylic acids

25
Q

explain how amino acid conjugation is different from the previous 2 (glucuronidation and sulfation)

A

the conjugating molecule (glutamine) just sits and waits while the substrate is being activated

in previous cases the conjugated group is activated and the substrate waits

26
Q

explain the mechanism of glutamine/amino acid conjugation

A

substrate + ATP -> substrate -O-AMP (AMP substrate ester)

AMP substrate ester reacts with CoA (has SH on its tail) to give ACYL COA + AMP that comes off

acyl coA reacts with the conjugating group (glutamine) which has been sitting and waiting which causes CoA-SH to come off

27
Q

the biological activity of histamine is terminated by____

A

methylation

28
Q

what are the typical substrates for GSH conjugation?

A

electron deficient (electrophilic), chemically reactive species that want to combine with a nucleophile

cysteine contains a THIOL (SH) functional group which is the MOST NUCLEOPHILIC GROUP at physiological pH

29
Q

Explain the mechanism of GSH conjugation

A

substrate (Benzyl Chloride in this case) reacts with GSH in the presence of GLUTATHIONE TRANSFERASE

the benzylic carbon is electrophilic and thus GSH attacks it and kicks chlorine out (good leaving group) and the initial conjugate is formed.

gamma glutamic acid comes off of this initial metabolite in the presence of Glutathionase, to give a cysteine-glycine dipeptide

with Peptidase (cysteinylglycianse), glycine comes off and the remaining molecule is the parent benzylic molecule with cysteine attached.

N-acetyl transferase incorporates an acetyl group to this molecule to give

BENZYLMERACPTURIC ACID — an acetylated cysteinyl conjugate is the end metabolite

30
Q

another name for glutathionase.
what does it do?

A

Y-glutamyl transpeptidase

removes Y-glutamic acid from the initial metabolite in GSH conjugation

31
Q

another name for peptidase

what does it do?

A

cysteinylglycinase

removes glycine from the cysteine-glycine dipeptide in GSH conjugation

32
Q

is nitro electron withdrawing or donating?

A

NO2
electron withdrawing

33
Q

are the halogens electron withdrawing or donating

A

withdrawing

34
Q

aromatic ring with an EWG – is it reactive enough for GSH conjugation?

A

no, but if you happen to have a halogen (Cl,Br, or I) with 2 extra EWGs, it is most likely reactive enough

could displace the bromine in GSH

35
Q

What is the activated conjugating group in methylation?

A

SAM

S-adenosylmethionine

36
Q

state the conjugation reaction for methylation
(only the conjugating reaction”

A

SAM + RZH (Z could be OH, NH, OR S) —> RZ-CH3 + S-adenosylhomocysteine

enzyme = methyl transferase

37
Q

what is the substrate for methylation?

A

RZH
Z = OH/NH/S

so basically either alcohol, amine, or thiol

38
Q

explain the ENTIRE PROCESS of methylation

A

step 1 – activate SAM (the conjugating group)

methionine is added to adenosine via METHIONINE ADENOSYL TRANSFERASE with the help of ATP. this produces SAM (S-adenosylmethionine)

SAM reacts with the substrate RZH to produce RZ-CH3 (substrate is methylated) via METHYL TRANSFERASE

SAM is now S-Adenosylhomocysteine

39
Q

which conjugation is more popular in our biological system (the body) rather than in the metabolism of ingested drugs?

A

methylation

the methylation of norepinephrine especially at the meta OH terminates the biological activity of norepinephrine

40
Q

explain the methylation of norepinephrine

A

SAM + norepinephrine —>
3-Methoxynorepinephrine

via COMT (catecholamine-o- methyl transferase) remember – biological activity especially terminated at meta position

if via PNMT (phenylethanolamine), the methyl group on SAM gets transferred to the NH on norepinephrine to produce epinephrine

41
Q

explain the specificity of acetylation

A

VERY LIMITED SPECIFICITY

typical substrate is a primary amine

R-NH2 and the NH2 MUST be the end terminal

42
Q

for __________phase 2 reactions, there is no enhancement of water solubility. The purpose is to terminate biological activitiy

A

methylation and acetylation and GSH conjugation

43
Q

what is the conjugating group activated by in acetylation?

A

acetyl CoA

44
Q

what is the catalyzing enzyme in acetylation?

A

acetyl transferase

45
Q

give an example of a specific drug that can undergo acetylation

A

isoniazid - ends in NH2

46
Q

what is the major metabolite of isoniazid?

A

acetyl isoniazide

-substrate for acetylation

47
Q

is acetyl isoniazide bioactive?

A

NO
it undergoes acetylation which terminates biological activity WITHOUT ENHANCING WATER SOLUBILITY

48
Q

What does UDPGA stand for?
how is it produced?

A

uridine disphosphate glucuronic acid
produced via UDPG dehydrogenase + 2NAD+

49
Q
A

Med Chem Final (11 decks)

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