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Tissues > T08 - Purine and Pyrimidine Metabolism > Flashcards

T08 - Purine and Pyrimidine Metabolism Flashcards

1
Q

What is the basic structure of purines?

A

9-membered heterocyclic, aromatic double ring w/ 5 carbons and 4 nitrogens

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2
Q

Draw the generic structure of a purine. Identify where substituents can be placed.

A
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3
Q

What are the oxopurines?

A

hypoxanthine (1 OH group)

xanthine (2 OH groups)

uric acid (3 OH groups)

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4
Q

What is the significance of hypoxanthine?

A

initial product of de novo purine synthesis

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5
Q

What is the significance of uric acid?

A

end product of purine degradation that is excreted in urine

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6
Q

Knowing the structure of the oxopurines, how are the aminopurines adenine and guanine produced?

A

replace the -OH group in hypoxanthine with -NH2 → adenine

replace one of the -OH groups in xanthine with -NH2 → guanine

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7
Q

What is the generic structure of pyrimidines?

A

single 6-membered heterocyclic ring w/ 2 nitrogens and 4 carbons

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8
Q

What is the initial product of pyrimidine biosynthesis?

A

orotic acid, the precursor of the other pyrimidines

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9
Q

What is the significance of orotic acid?

A

initial product of pyrimidine biosynthesis, therefore the precursor to other pyrimidines

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10
Q

(T/F) Orotic acid’s only metabolic purpose is to serve as a pyrimidine precursor.

A

True. It does not have any other metabolic functions.

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11
Q

Decarboxylation of orotic acid produces

A

uracil

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12
Q

Substituting a keto group of uracil with an amino group yields

A

cytosine

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13
Q

What is the relationship between cytosine, thymine, uracil?

A

cytosine is deaminated to produce uracil

uracil is methylated to produce thymine

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14
Q

Differentiate between the terms nucleoside, ribonucleoside, ribonucleotide, and deoxyribonucleotide.

A

nucleoside = nitrogenous base

ribonucleoside = nitrogenous base + sugar (ribose)

ribonucleotide = nitrogenous base + sugar + 1 or more phosphate

deoxyribonucleotide = ribonucleotide with -OH at 2 position removed by ribonucleotide reductase

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15
Q

Write out the corresponding nucleosides and nucleotides for adenine.

A

adenine → adenosine → adenylate

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16
Q

Write out the corresponding nucleosides and nucleotides for guanine.

A

guanine → guanosine → guanylate

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17
Q

Write out the corresponding nucleosides and nucleotides for hypoxanthine.

A

hypoxanthine → inosine → inosinate

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18
Q

Write out the corresponding nucleosides and nucleotides for xanthine.

A

xanthine → xanthosine → xanthinate

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19
Q

What four compounds make up the purines?

A

adenine

guanine

hypoxanthine

xanthine

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20
Q

Write out the corresponding nucleosides and nucleotides for uracil.

A

uracil → uridine → uridylate

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21
Q

Write out the corresponding nucleosides and nucleotides for cytosine.

A

cytosine → cytidine → cytidylate

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22
Q

Write out the corresponding nucleosides and nucleotides for thymine.

A

thymine → thymidine → thymidylate

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23
Q

What three compounds make up the pyrimidines?

A

uracil

cytosine

thymine

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24
Q

Which form is most commonly encountered in cells — bases, nucleosides, or nucleotides?

A

nucleotides are most commonly encountered

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25
Q

How are purines primarily synthesized (i.e. what form do they assume)?

A

synthesized as inosine monophosphate (IMP), an example of a ribonucleotide monophosphate (rather than free base)

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26
Q

What are the carbon/nitrogen sources to form the purine ring?

A

glycine

aspartate

glutamine

formyl-tetrahydrofolate

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27
Q

Write out the equation of the first step of purine synthesis.

A

glutamine + PRPP → phosphoribosylamine + glutamate + PPi

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28
Q

What enzyme catalyzes the first dedicated step of purine synthesis?

A

PRPP amidotransferase

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29
Q

Describe the reversibility of the first dedicated step of purine synthesis.

A

irreversible, because of hydrolysis of pyrophosphate bond

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30
Q

What is the second step of purine synthesis?

A

phosphoribosylamine → formation of first 5-membered ring → formation of second 6-membered ring → inosine monophosphate

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31
Q

Inosine monophosphate is a common precursor for which two compounds?

A

adenosine monophosphate (an adenylate)

guanosine monophosphate (a guanylate)

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32
Q

How is IMP converted to AMP?

A

replace the carbonyl group of IMP with an amino group

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33
Q

The net synthesis of AMP from phosphoribosylamine consumes how many phosphates?

A

4 phosphates consumed:

2 to make the 5-membered ring

1 to make the 6-membered ring (i.e. form IMP)

1 to replace IMP C=O group w/ NH2 (i.e. form AMP)

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34
Q

How is IMP converted to GMP?

A

add C=O to form XMP

then add NH2 to form GMP

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35
Q

The net synthesis of GMP from phosphoribosylamine consumes how many phosphates?

A

5 phosphates consumed:

2 to make the 5-membered ring

1 to make the 6-membered ring (i.e. form IMP)

2 for IMP → XMP → GMP

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36
Q

How are the syntheses of AMP and GMP kept in balance?

A

reciprocal regulation:

AMP synthesis requires GTP and is feedback-inhibited by AMP

GMP synthesis requires ATP and is feedback-inhibited by GMP

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37
Q

AMP and GMP reciprocally regulate their syntheses. However, what happens if both AMP and GMP levels are high?

A

IMP (the precursor) will be degraded and excreted as uric acid instead of making more AMP/GMP

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38
Q

How is purine synthesis enzymatically regulated?

A

control of glutamine-PRPP amidotransferase:

  • binding of substrate (PRPP) → conformational change in enzyme → increases activity
  • enzyme is allosterically feedback-inhibited by purines
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39
Q

A defect in the feedback inhibition of glutamine-PRPP amidotransferase results in

A

gout:

faulty feedback inhibition → overproduction of purines → increased uric acid formation

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40
Q

What are salvage reactions?

A

reusing bases or nucleosides to reform nucleotides

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41
Q

What are the two purine salvage enzymes?

A

hypoxanthine/guanine phosphoribosyltransferase (HPRT)

adenine phosphoribosyltransferase (APRT)

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42
Q

What are the reactions catalyzed by hypoxanthine/guanine phosphoribosyltransferase (HPRT)?

A

hypoxanthine + PRPP → IMP + PPi

guanine + PRPP → GMP + PPi

43
Q

What is the reaction catalyzed by adenine phosphoribosyltransferase (APRT)?

A

adenine + PRPP → AMP + PPi

44
Q

What is Lesch-Nyhan syndrome?

A

a deficiency of the hypoxanthine/guanine phosphoribosyltransferase (HPRT) enzyme

45
Q

What is the clinical result of Lesch-Nyhan syndrome?

A

accumulation of hypoxanthine and guanine → degraded → high uric acid levels

46
Q

What is the presentation of Lesch-Nyhan syndrome? (2)

A

severe neurological defects

self-injurious behavior

47
Q

What is the inheritance pattern of Lesch-Nyhan syndrome?

A

X-linked recessive

48
Q

How are nucleotides converted to nucleosides?

A

using 5’ nucleotidases:

e.g. AMP → adenosine + Pi

49
Q

How are nucleosides converted to bases?

A

by nucleoside phosphorylases:

e.x. guanosine + Pi → guanine + ribose-5-phosphate

50
Q

(T/F) Adenylate cannot be directly converted to guanylate.

A

True. Conversion must go through IMP.

51
Q

(T/F) Adenine can be deaminated.

A

False. Adenine cannot be deaminated.

52
Q

List the steps in the conversion of hypoxanthine to uric acid.

A

hypoxanthine → [oxidation via xanthine oxidase] → xanthine → [oxidation via xanthine oxidase] → uric acid

53
Q

How is gout treated?

A

with allopurinol, a hypoxanthine analog that acts as a suicide substrate of xanthine oxidase

54
Q

What is the relationship between guanine and xanthine?

A

guanine can be deaminated to form xanthine

55
Q

Draw out the overall pathway(s) of purine synthesis/degradation.

56
Q

What is an important difference in the early synthesis of pyrimidines versus purines?

A

pyrimidines are synthesized as free bases, not bound to a sugar + phosphate (as is the case for purines)

57
Q

What are the initial products of pyrimidine nucleotide synthesis?

A

orotate → orotidylate (a.k.a. orotidine monophosphate) [precursor pyrimidine] → other pyrimidines

58
Q

Draw a diagram that shows the origins of the carbons and nitrogens in a pyrimidine ring.

59
Q

What is the first step in pyrimidine synthesis?

A

synthesis of carbamylphosphate

60
Q

What enzyme catalyzes the first step of pyrimidine synthesis?

A

carbamylphosphate synthetase II (CPS2)

61
Q

How does CPS2 in pyrimidine synthesis differ from CPS1 in ureagenesis? (3)

A

CPS2:

cytosolic

uses glutamine as a nitrogen source

does not require N-acetylglutamate as an activator

62
Q

What is the second step of pyrimidine synthesis?

A

combining carbamylphosphate + aspartate

63
Q

What catalyzes the second step of pyrimidine synthesis?

A

aspartate transcarbamylase (ATCase)

64
Q

What is the third step of pyrimidine synthesis?

A

dehydration reaction that closes ring → formation of dihydroorotate

65
Q

Describe how the enzymes that catalyze the first three steps of pyrimidine synthesis are encoded.

A

CPS2, ATCase, and dihydroorotase are encoded by CAD, a single polypeptide

66
Q

What enzyme catalyzes the third step of pyrimidine synthesis?

A

dihydroorotase

67
Q

After dihydroorotate is formed after the first 3 steps of pyrimidine synthesis, what further processing does it undergo?

A

dihydroorotate → [dehydrogenation] → orotate → [ribose/phosphate transfer] → orotidylate → [decarboxylation] → urdiylate monophosphate (UMP)

68
Q

List out the overall intermediates in pyrimidine synthesis.

A

carbamyl phosphate → some ring-like structure → dihydroorotate (closed ring) → orotate → orotidylate → uridylate monophosphate

69
Q

What catalyzes the conversion of dihydroorotate to UMP?

A

dihydroorotate dehydrogenase

UMP synthase (catalyzes orotate → orotidylate and orotidylate → UMP)

70
Q

How is cytidine synthesized?

A

add amino group to UTP (addition must occur at nucleoside triphosphate level)

71
Q

What is the nitrogen source in cytidine synthesis?

72
Q

How is pyrimidine nucleotide synthesis regulated?

A

via CPS2:

inhibited by UTP

activated by PRPP

73
Q

How are pyrimidine bases salvaged to reform nucleotides?

A

uracil + PRPP → UMP + PPi (catalyzed by UMP synthase)

74
Q

What enzyme synthesizes all four deoxyribonucleotides?

A

ribonucleotide reductase

75
Q

Deoxyribonucleotide synthesis requires what cofactor?

A

requires NADPH for reducing power

76
Q

What are the substrates for the ribonucleotide reductase reaction?

A

ADP, GDP, CDP, UDP

77
Q

What is the major inhibitor of ribonucleotide reductase?

78
Q

Thymidine, a nucleoside, can exist only in what nucleotidic form?

A

only exists as a deoxyribonucleotide

79
Q

How is deoxythymidylate synthesized? (2)

A

UDP → [ribonucleotide reductase] → dUDP → dUMP → [thymidylate synthase] → dTMP

or

dCMP → [deamination] → dUMP → [thymidylate synthase] → dTMP

80
Q

What supplies the methyl group of thymidine?

A

5,10-methylenetetrahydrofolate

81
Q

What is the significance of 5,10-methylenetetrahydrofolate in terms of deoxyribonucleotide synthesis and cancer therapy?

A

the 5,10-methylenetetrahydrofolate reaction is the main target of methotrexate and antifolates → reduces dTMP synthesis → inhibits cell division

82
Q

What compounds are released when pyrimidines are degraded?

A

beta-amino acids

CO2

ammonia

83
Q

Write out the pathway of uracil degradation. (3)

A

uracil → dihydrouracil → beta-alanine

84
Q

Write out the pathway of thymine degradation.

A

thymine → dihydrothymine → beta-aminoisobutyric acid

85
Q

How does the oxidation of allopurinol alleviate gout?

A

allopurinol → [oxidation] → oxypurinol, which can’t be further oxidized by xanthine oxidase because of the position of the nitrogen, so it stops xanthine oxidase activity

86
Q

Differentiate between xanthine and hypoxanthine in terms of solubility.

A

hypoxanthine = highly soluble

xanthine = not soluble

87
Q

Allopurinol can treat gout by inhibiting xanthine oxidase. What is another pathway/mechanism by which allopurinol can treat gout? (4)

A

allopurinol → [HPRT enzyme] → allopurinol ribonucleotide → allosterically inhibits PRPP synthetase/glutamine-PRPP amidotransferase → decreases overall purine synthesis

88
Q

What are antimetabolites?

A

structural analogs of bases or nucleotides

89
Q

Write out the pathway of 6-mercaptopurine (6MP) action.

A

azathioprine → 6MP → [HPRT enzyme] → 6MP ribonucleotide → feedback inhibition of glutamine-PRPP amidotransferase → inhibition of purine synthesis

90
Q

What inactivates 6-mercaptopurine?

A

xanthine oxidase

91
Q

Write out the pathway of 5-fluorouracil (5FU) action.

A

5FU → 5FU ribonucleotide triphosphate (5FUTP) → incorporated into mRNA → inhibits maturation of m/rRNA

92
Q

What inhibits thymidylate synthase?

93
Q

Write out the pathway of cytosine arabinoside (AraC) action. (4)

A

AraC, a nucleoside → Ara-CTP, a nucleotide → incorporated into DNA instead of CTP → blocks DNA synthesis

94
Q

Why isn’t methotrexate used to treat gout?

95
Q

What is a side effect of methotrexate treatment?

A

reduction in synthesis of methionine, causing homocysteine to accumulate (homocystinuria)

96
Q

What is leukovorin?

A

formyl-THF that is more stable in air and used to “rescue” normal cells following methotrexate treatment

97
Q

What is acyclovir?

A

inactive analog of GMP that functions as an antiviral agent

98
Q

What is aminopterin?

A

a drug not used today that has similar effects to methotrexate

99
Q

What is the active form of acyclovir?

A

acyclovir triphosphate

100
Q

Write out the pathway of acyclovir action.

A

acyclovir → [phosphorylated in infected cells by thymidine kinase] → acyclovir triphosphate → inhibits DNA synthesis

101
Q

Describe the function of nucleotide analogs azidothymidine (AZT) and dideoxyionsine (ddI).

A

used to treat HIV because of ability to inhibit reverse transcriptase

102
Q

Describe the use of ganciclovir.

A

used to treat cytomegalovirus (CMV) infections

103
Q

Describe the use of ribavirin. (2)

A

used to treat respiratory syncytial virus (RSV)

used to treat hep C infections

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