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Biochemistry II > Nucleotide metabolism II > Flashcards

Nucleotide metabolism II Flashcards

1
Q

Draw the structures of the 2 purine bases.

A
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2
Q

Draw the structures of the 3 pyrimidine bases.

A
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3
Q

Describe the basic scheme of the de novo synthesis of the 2 pyrimidine nucleotides.

A

use UMP as common precursor

  1. de novo synthesis of UMP
  2. … → UTP
  3. … → CTP
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4
Q

Which enzymes are involved in the de novo synthesis of UMP?

Cellular location?

A

3 enzymes

  • CAD complex: multifunctional enzyme, step 1-3
    → in cytosol
  • dihydroorotate dehydrogenase: step 4
    → in inner mitochondrial membrane
  • UMP synthase: multifunctional enzyme, step 5-6
    ​→ in cytosol
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5
Q

The CAD complex is a multifunctional enzyme.

What are its 3 activities?

A
  • carbamoyl-P synthetase II
  • Asp transcarbamoylase
  • dihydroorotase

<u><strong>​</strong>NOTE:</u> in urea cycle step 1 and 2 catalyzed by carbamoyl-P synthetase I and ornithine transcarbamoylase

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6
Q

UMP synthase is also a multifunctional enzyme.

What are its 2 activities?

A
  • orotate phosphoribosyl transferase (OPRT)
  • oritidylate (OMP) decarboxylase
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7
Q

Which structures form the pyrimidine ring system?

A
  • carbamoyl-phosphate
  • Asp
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8
Q

The enzyme activity of which enzyme is needed to catalyze the first step of pyrimidine nucleotide synthesis?

Reaction.

Where does it happen?

A

Carbamoyl-P synthetase II (CPS II) (CAD)
in cytosol

CO2 + Gln + 2ATP + H2O
→ Glu + 2ADP + Pi + carbamoyl-P

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9
Q

What happens to carbamoyl-P during the de novo synthesis of pyrimidine nucleotides?

Enzyme + reaction.

Where does it happen?

A

Asp transcarbamoylase (CAD)
in cytosol

carbamoyl-P + Asp → carbamoyl-Asp + Pi

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10
Q

What happens to carbamoyl-Asp during the de novo synthesis of pyrimidine nucleotides?

Enzyme + reaction.

Where does it happen?

A

dihydroorotase (CAD)
in cytosol

carbamoyl-Asp → dihydroorotate + H2O

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11
Q

What happens to dihydroorotate during the de novo synthesis of pyrimidine nucleotides?

Enzyme + reaction.

Where does it happen?

A

dihydroorotate dehydrogenase
on inner mitochondrial membrane

dihydroorotate + NAD+ → orotate + NADH

<u>NOTE:</u> ubiquinone used as electron acceptor

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12
Q

What happens to orotate during the de novo synthesis of pyrimidine nucleotides?

Enzyme + reaction.

Where does it happen?

A

orotate phosphoribosyl transferase (UMP-synthase)
in cytosol

orotate + PRPP → orotidylate (OMP) + PPi

<u>NOTE:</u> same concept as for purines:<br></br>base + PRPP → nucleotide + PPi

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13
Q

What happens to orotidylate during the de novo synthesis of pyrimidine nucleotides?

Enzyme + reaction.

Where does it happen?

A

oritidylate (OMP) decarboxylase (UMP-S)
in cytosol

OMP → CO2 + uridine monophosphate (UMP)

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14
Q

How is UTP formed?

Which enzymes catalyze those reactions?

A

in 2 steps

  1. UMP kinase:
    UMP + ATP → UDP + ADP
  2. UDP kinase:
    UDP + ATP → UTP + ADP
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15
Q

How is CTP formed?

Enzyme + reaction.

A

CTP synthetase

UTP + ATP + Gln + H2O → ADP + Pi + Glu + CTP

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16
Q

Which enzyme catalyzes the rate-limiting step of de novo pyrimidine synthesis?

A

carbamoyl-P synthetase 2

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17
Q

Which substances regulate the activity of the CAD complex?

A

​allosteric regulation

  • inhibited by UTP (product)
  • activated by PRPP (also substrate of purine synthesis → if we have many purines, we also need pyrimidines for base pairing)
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18
Q

Which substances are able to regulate the activity of UMP synthase?

A

inhibited by UMP (product)

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19
Q

What is the consequence of hereditary UMP-S deficiency?

How is it treated?

Symptoms?

A

causes oritic aciduria
no formation of UTP, but orotate accumulates → disinhibition of CAD → incr. orotate production, eventually excreted via urine

  • treatment: oral uridine
  • symptoms: megaloblastic anemia, delayed physical/intellectual development, leukopenia (↓ leukocytes), early death
20
Q

Which substances are inhibitors of UMP-S?

Consequence?

A
  • allopurinol: used to treat gout
  • 6-azauridine: synthetic nucleotide analog, used in cancer treatment

→ inhibition of UMP-S leads to orotic aciduria (same mechanism as UMP-S deficiency)

21
Q

What is the consequence of an ornithine transcarbamoylase deficiency?

Mechanism.

A

reason for hyperammonemia type II
+ also causes orotic aciduria

carbamoyl-P not used in urea cycle, accumulates → used by CAD instead → incr. orotate formation + excretion

22
Q

What is the difference btw purine and pyrimidine salvage reactions?

A
  • purine salvage reactions:
    • purine bases → nucleotides
    • esp. important in extrahepatic tissues b/c are unable to undergo de novo synthesis
  • pyrimidine salvage reactions:
    • pyrimidine nucleosides → nucleotides
    • not as important as purine salvage RXNs b/c all tissues can do de novo synthesis

⇒ pyrimidine nucleosides only require phosphorylation

23
Q

Describe the mechanism of pyrimidine salvage reactions.

A
  • UMP/CMP can be recovered directly
    urdine/cytidine kinase
    uridine/cytidine + ATP → UMP/CMP + ADP
  • CMP can also be converted to UMP
    cytidilate deaminase
    CMP + H2O → UMP + NH3
24
Q

Describe the general scheme of pyrimidine nucleotide catabolism.

A
  1. pyrimidine nucleotides → pyrimidine nucleosides
  2. transported via blood to liver/kidney
  3. … → pyrimidine bases
  4. … multiple steps → CO2, NH3, _β-_Ala
25
Q

Which groups of enzymes catalyzes the catabolism of pyrimidine nucleotides?

Reaction scheme.

Individual reaction products.

A

5’ nucleotidase
specific for each nucleotide

monophosphate nucleotide → nucleoside + Pi

  • UMP → uridine
  • dTMP → thymidine
  • CMP → cytidine

just like purine catabolism

26
Q

Which groups of enzymes catalyzes the catabolism of pyrimidine nucleosides?

Reaction scheme.

Individual reaction products.

A

pyrimidine nucleotide phosphorylases
specific for each nucleoside

nucleoside + Pi → pyrimidine base + sugar

  • uridine → uracil + ribose-1P
  • thymidine → thymine + dribose-1P
    NOTE: since thymin only exists in DNA, there is no oxy-version

besides that same mechanism as for purines

27
Q

One pyrimidine nucleoside is not catabolized as described earlier.

Which one?

Enzyme + reaction.

A

cytidine deaminase

cytidine + H2O → uridine + NH3

28
Q

Which C atom of deoxynucleotides is the deoxygenated one?

Consequence?

A

C2

⇒ DNA is less prone to hydrolysis due to missing -OH group (ergo more stable)

29
Q

How are deoxyribonucleotides produced?

Enzyme + reaction.

What would be a prerequisite for this reaction to happen?

A

ribonucleotide reductase

NDP → dNDP + H2O

BUT: has to be _reduced firs_t, by either of the 2 mechanisms:

  • tioredoxin
  • glutaredoxin
30
Q

Describe the structure of ribonucleotide reductase.

When is it active?

A

ribonucleotide reductase (RR)
dimer

  • R1-subunit: catalytic subunit, const. expressed
  • R2-subunit: regulatory subunit, induced by E2F transcription factor

⇒ only active during S phase of cell cycle
(dividing cells)

31
Q

How does tioredoxin help to reduce ribonucleotide reductase?

Describe the pathway.

A
  1. NADPH used to reduce FAD of tioredoxine reductase to FADH2
  2. tioredoxine reductase:
    used to reduce Trx-S2 to Trx(SH)2
  3. used to reduce ribonucleotide reductase-S to RR(SH)2

⇒ ribonucleotide reductase then catalyzes dNDP formation

32
Q

How does glutaredoxin help to reduce ribonucleotide reductase?

Describe the pathway.

A
  1. NADPH used to reduce glutatione
  2. glutathione reductase:
    used to reduce glutaredoxin-S2 to Grx(SH)2
  3. used to reduce ribonucleotide reductase-S to RR(SH)2

⇒ ribonucleotide reductase then catalyzes dNDP formation

33
Q

Describe the allosteric regulation of RR.

A

2 types of regulation:

  • complete inhibition: by dATP
  • change of ratio of dNTP synthesis
    • dTTP = ↑dGTP, ↓dTTP/dCTP
  • dGTP = ↑dATP, ↓dGTP/dTTP/dCTP
  • → NO formation of any dNTPs
34
Q

The ribonucleotide reductase forms dNDPs.

But how do they become dNTPs?

List the individual products.

A

phosphorylated by kinases

dNDP + ATP → dNTP + ADP

  • dADP → dATP
  • dGDP → dGTP
  • dCDP → dCTP
35
Q

There is one dNTP which is not formed by phosphorylation from its dNDP.

How is it formed instead?

A
  1. dUDP → dUMP (otherwise higher risk for accidental incorporation into DNA) to
  2. thymidylate synthase
    dUMP + methylene H4F → dTMP + H2F
  3. eventually phosphorylated twice by kinases
    dTMP →→ dTTP
36
Q

What does 5-fluoro-dUMP do?

A

synthetic nucleotide analog:

cannot be converted to dTMP, hence inhibiting thymidilate synthase

→ treatment of colon cancer

37
Q

How is CH2-H4F restored after synthesis of dTMP?

Enzyme + reactions.

A

folate cycle

  1. dihydrofolate reductase
    H2F + NADPH → H4F + NADP+
  2. CH-H4F + Ser/Gly → CH2-H4F + H2O

⇒ eventually methylene-H4F​ can be used again for dTMP synthesis or continue further in folate cycle

38
Q

What does methotrexate do?

A

folate antagonists

inhibit dihydrofolate reductase which is required to restore H4F, hence dTMP cannot be generated

→ used in tumor therapy

39
Q

Explain the function of sulphonamides.

A
  • humans: acquire essential vitamine folate through diet
  • bacteria: synthesize folate

⇒ sulphonamides inhibit synthesis of folate → inhibit growth/proliferation of bacteria

= antibacterial effect

40
Q

There are also salvage reactions for deoxynucleotides.

Any similarites to the salvage reactions of purine/pyrimidine nucleotides?

Individual products.

A

same mechanism as pyrimidine salvage reactions:

deoxynucleoside + ATP → dNMP + ADP

  • dcytidine → dCMP
  • dadenine → dAMP
  • dguanine → dGMP
  • thymidine → dTMP
41
Q

Which enzymes catalyze those deoxy salvage reactions?

A
  • deoxycytidine kinase (dCK)
  • thymidine kinase (dTK)
42
Q

Which reaction is catalyzed by dCK?

Characteristics.

A

deoxycytidine kinase (dCK)

deoxycytidine + ATP → dCMP + ADP

  • lymphoid specific
  • broad substrate specificity
  • *dAde, dGua, dCyt**
43
Q

Explain the function of antileucemic agents acting on deoxycitidine kinase

Examples.

A

= deoxynucleotide (substrates for dCK) analogues
→cannot be converted to physiological dNMPs

  • arabinosyl-cytosine
  • 2-chloro-deoxyadenosine
44
Q

Which reaction is catalyzed by dTK?

Characteristics.

A

thymidine kinase (dTK)

thymidine + ATP → ADP + dTMP

  • S-phase dependent enzyme
  • substrate specific
45
Q

What is an antiviral medication for the herpes simplex virus?

Why?

A
  • human dTK: substrate specific
  • HSV dTK: wide substrate specificity

→ selective inhibition w/ nucleoside analogues (aciclovir)

46
Q

How can the earlier described dTK version of the herpes simplex virus be clinically useful?

A

can be transfected into T lymphocytes, then ganciclovir administered to selectively kill them

→ used for treatment of acquired immunodeficiencies (e.g. AIDS)

Biochemistry II (16 decks)

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