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CORE Block 5 > Purine and pyrimidine nucleotides > Flashcards

Purine and pyrimidine nucleotides Flashcards

1
Q

2 components of nucleotide:

A
  1. nitrogen base
  2. sugar
  3. phosphate group
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2
Q

Compare numerations in purines and pyrimidines.

A

In pyrimidines, numeration is clockwise. In purines, numeration is counterclockwise

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3
Q

How are pyrimidines similar to purines?

A

Purines are essentially a pyrimidine plus an imidazole.

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4
Q

Adenine

A
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5
Q

Guanine

A
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6
Q

Hypoxanthine

A

oxidized adenine

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7
Q

xanthine

A

oxidized guanine

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8
Q

Is caffeine a purine or pyrimidine?

A

Purine

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9
Q

In what pathways are the purines xanthine and hypoxanthine involved?

A

Purine biosynthesis and degradation

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10
Q

Why is the concentration of free nitrogen bases in the cell normally low?

A

They are normally found as nucleosides (sugar plus base) or as nucleotides.

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11
Q

Uracil

A
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12
Q

Thymine

A

methyl uracil

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13
Q

Cytosine

A
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14
Q

Orotic acid

A
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15
Q

For what is orotic acid used?

A

An intermediate during pyrimidine biosynthesis

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16
Q

Hydrogen bonding between nitrogen bases contributes to their flatness. Why is this important?

A

It allows DNA to be more stable because flatness allows for base stacking.

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17
Q

Define nucleoside.

A

Nitrogen base + sugar

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18
Q

At which carbon do ribose and deoxyribose differ?

A

Deoxyribose does not have a hydroxyl group at carbon 2

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19
Q

In what configuration is the glycosidic linkage in nucleosides?

A

It is always beta, placing the nitrogen base above the sugar.

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20
Q

Describe the nucleoside nomenclature, and the exception for the rule.

A

uracil + ribose = uridine (pyrimidines end in -idine)

adenine + ribose = guanosine (purines end in -osine)

+ DNA = deoxyguanosine (dGMP)

exception: hypoxanthine + ribose = inosine

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21
Q

Nomenclature difference between nucleoside and nucleotide.

A

adenine base + sugar = adenosine

adenine + sugar + phosphate = adenosine monophosphate (AMP)

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22
Q

To which carbon of nucleosides do phosphate groups bind?

A

They can bind to the 3’ or 5’ carbon. In the case of cAMP, phosphate binds to both positions to cyclize the molecule. In DNA, phosphate binds to the 5’ carbon

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23
Q

Why are phosphates used to link nucleosides in DNA or RNA?

A

phosphoric acid can link two nucleotides and still ionize:

  • the charge can stabilize the ester against hydrolysis
  • the charge can retain the molecule within a lipid membrane, because the charge cannot pass the membrane

Phosphate monoesters are also very stable with a long half life, allowing for the formation of very long polynucleotides

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24
Q

List the functions of purines and pyrimidines in the cell.

A
  1. storage of genetic information
  2. inhibitors of DNA synthesis
  3. universal source of energy
  4. activated intermediates of biosynthetic pathways
  5. components of coenzymes
  6. intracellular signaling molecules
  7. regulators of metabolism
  8. activated donors
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25
Q

Describe how nucleotides can act to treat HIV.

A

AZT and DDI both lack hydroxyl group at carbon 3’, so DNA synthesis cannot continue when they are present.

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26
Q

What nucleotide is a universal source of energy?

A

ATP

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27
Q

How do nucleotides act as activated intermediates of biosynthetic pathways, and what is an example?

A

Ex: UDP-glucose

  • provides energy for glycosylation
  • provides energy for storage of energy in glycogen
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28
Q

Describe nucleotides that are components of coenzymes.

A

NAD and FADH2 coenzyme cosubstrates contain nucleotides (adenine specifically)

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29
Q

Describe how nucleotides can act as intracellular signaling molecules.

A

cAMP – universal second messenger (regulates glycogen metabolism in response to glucagon, signals for degradation of glycogen)

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30
Q

Describe how nucleotides can be used as regulators of metabolism.

A

Allosteric effector AMP acts as a low energy signal to activate PFK in phosphorylation of F6P to F1,6DP

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31
Q

How do nucleotides act as activated donors?

A
  • SAM acts as a methyl donor for histone methylation and DNA methylation
  • PAPS acts as a sulfate donor
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32
Q

What are the sources of purine and pyrimidine nucleotides?

A
  • de novo (major pathway)
  • salvage pathway (minor pathway)
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33
Q

Describe abiotic synthesis of adenine.

A

Low efficiency, not used inside cells.

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34
Q

How was it determined that de novo synthesis of purines were made from small molecule precursors?

A
  • pigeons and rats received radiolabelled bicarbonate, formate, and glycine
  • excreted purines were isolated and chemically degraded, revealing labelled carbon and nitrogen in specific locations of the ring
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35
Q

List the source of the carbon and nitrogen positions in the purine ring.

A
36
Q

What is the source of ribose in all nucleotides, purines and pyrimidines?

A

PRRP (phosphoribosyl pyrophosphate)

37
Q

Generally, how is the ring structure of hypoxanthine purine synthesized?

A

It is not synthesized as a free base, but as 5’-inosine monophosphate with PRRP being the ribose source.

38
Q

What is the parent purine in purine biosynthesis?

A

IMP (5’-inosine monophosphate)

39
Q

Describe the key regulated and committed step of purine biosynthesis.

A

The first step. Substrate channeling.

  1. Amine group of glutamine attacks nucleophilic carbon 1’ of PRPP, kicking phosphate off PRRP and forming glutamate. Final product shown.
40
Q

What are the two functions of PRPP?

A
  1. substrate in purine biosynthesis
  2. activator (positive regulation of first step of purine synthesis)
41
Q

Why is PRPP alpha configuration switched to beta configuration in the first step of purine synthesis?

A

Nucleophilic substitution of the amine group (SN2). Amino group adds to the face of the carbon atom opposite the pyrophosphate leaving group.

42
Q

Describe regulation of the first step of purine synthesis.

A
  • negative feedback inhibition (IMP, AMP, GMP)
  • positive PRPP regulation
43
Q

What is the most common type of reaction of nucleotide synthesis?

A

Nucleophilic substitution

44
Q

Describe the second regulated step of purine synthesis.

A

1’ amino group on ribosylamine attacks carbonyl of glycine, after the carbonyl is activated with a phosphate from ATP to form a good leaving group. Final product is glycinamide ribosyl 5-phosphate.

45
Q

What do the enzymes in nucleotide synthesis that involve ATP activation have in common?

A

They have ATP grasp domains.

46
Q

How are ATP and GTP formed from parent purine IMP?

A

First, AMP and GMP are formed. Using monophosphokinase and a nucleoside, GMP can be converted to GDP. Then using diphosphokinase and a nucleoside, GDP can be converted to GTP.

47
Q

Difference between monophosphokinase and diphosphokinase beyond substrate?

A

mono is specific for each NMP, but not for the sugar. di has broad NMP specificity.

48
Q

How is AMP formed from parent purine IMP?

A

Hypoxanthine carbonyl oxygen is activated with phosphate from GTP to form a good leaving group. Amino from aspartate then attacks the carbon, causing phosphate to leave. Fumerate then leaves, leaving behind amine from aspartate and an AMP molecule.

49
Q

Why is GTP used to activate IMP in process of forming AMP?

A

If we are making AMP, there likely is not ATP available to activate the carbonyl oxygen.

50
Q

How is GMP formed from IMP?

A

Hypoxanthine is first converted to xanthine (oxidation of hypoxanthine carbon by reduction of NAD). New carbonyl oxygen is activated with ATP to form good leaving group, and carbonyl carbon is attacked with amine from glutamine, forming GMP.

51
Q

How is conversion of IMP to ATP and GTP regulated?

A
  • ATP inhibits ASMP production, and GTP inhibits XMP production
  • conversely, ATP activates XMP production and GTP activates ASMP production
52
Q

Describe interconversion between adenine and guanine nucleotides.

A

Interconversions must go through IMP, not directly. AMP to IMP requires AMP deaminase. GMP to IMP requires GMP reductase.

53
Q

How are dATP and dGTP formed from ATP and GTP?

A

Deoxyribonucleotides are formed from ribonucleoside diphosphate. Ribonucleotide reductase reduces the 2’ carbon, with the electron source being thioredoxin. Oxidized thioredoxin is then re-reduced using electrons from NADPH.

54
Q

How is the reduction of guanosine to deoxyguanosine regulated?

A

dNTPs are only needed when the cell is getting ready to replicate.

  • dTTP positively affects ribonucleotide reductase
  • dGTP, dATP (inhibits ribonucleotide reductase for all dNTPs), hydroxyurea (pharmacological inhibitor) negatively affect ribonucleotide reductase
55
Q

Describe the salvage purine synthesis pathway in very simple terms.

A

Nitrogen base from nutrition or tissue recycling is directly added to activated PRPP.

56
Q

Describe reactions involved in adenine salvage pathway.

A

Adenine phosphoribosyl transferase (APRT) catalyzes addition of adenine to PRPP to form AMP and pyrophosphate, with the energy source being the bond between the first and second phosphates.

57
Q

Describe reactions involved in hypoxanthine or guanine salvage pathway.

A

hypoxanthine-guanine phosphoribosyl transferase (HGPRT) catalyzes addition of hypoxanthine or guanine to PRPP, resulting in formation of IMP or GMP and pyrophosphate

58
Q

What is caused by HGPRT deficiency?

A

Lesch-Nyhan disease. X-linked disorder where HGPRT is virtually absent. Increase in PRPP and ultimately uric acid, leading to gout and further symptoms.

59
Q

What is the main difference between purine and pyrimidine syntheses?

A

Purine: ring is made onto PRPP

Pyrimidine: ring is made first, then added to PRPP

60
Q

Describe the regulation of carbamoyl phosphate synthetase (CPS) in pyrimidine synthesis, and which step is affected.

A

Conversion of bicarbonate to carboxyphosphate with phsphate from ATP is regulated.

  • positively affected by PRPP
  • negatively affected by UTP
61
Q

The first three steps of pyrimidine synthesis are catalyzed by what complex?

A

CPS (carbamoyl phosphate synthetase)

62
Q

Describe carbamoyl phosphate synthetase (CPS).

A
  • glutamine hydrolysis domain
  • bicarbonate phosphorylation site
  • carbamic acid phosphorylation site
  • two ATP grasp domains (for the two ATP used in activation)
63
Q

What larger complex is CPS a member of?

A

CAD, a single, trifunctional protein

64
Q

Which CPS-catalyzed step in pyrimidine synthesis does not require ATP?

A

Carboxyphosphate to carbamic acid, because the phosphate is a good leaving group and the energy is provided in its hydrolysis.

65
Q

Which amino acid provides the nitrogen in carbamic acid in pyrimidine synthesis?

A

glutamine

66
Q

What is the committed step in pyrimidine synthesis?

A

Conversion of carbamoyl phosphate to carbamoyl aspartic acid using aspartate and energy from phosphate bond hydrolysis. (catalyzed by CAD)

67
Q

Once orotic acid nitrogen base is formed, how is UMP (uracil monophosphate) formed?

A

Orotic acid base is added to PRPP, with energy from loss of 1’ pyrophosphate. Orotic acid carboxylic acid is removed by orotidylate decarboxylase to form UMP, the parental pyrimidine.

68
Q

Describe the conversion of UTP to CTP.

A

Uracil carbon four carbonyl is activated with ATP by cytidylate synthetase, and glutamine amino group attacks carbonyl carbon, producing CTP.

69
Q

Describe the conversion of UMP to dUMP.

A

Ribonucleotide reductase is used as it was for the reduction of purines nucleotides. Reduction of pyrimidines is only carried out at the diphosphate level.

70
Q

Describe conversion of dUMP to dTMP.

A

This conversion can only take place in the monophosphate form of the nucleotide. Thymidylate synthase catalyzes the addition of a methyl group to dUMP, forming dTMP.

71
Q

Describe the transfer of methyl group to dUMP in formation of dTMP.

A
  • methyl is added from serine to tetrahydrofolate
  • methyl is then transferred to dUMP, catalyzed by thymidylate synthase
  • leftover dihydrofolate is then reduced by NADPH to recycle tetrahydrofolate
72
Q

Important inhibitors of dTMP synthesis

A
  • thymidylate synthase is inhibited by 5-fluorouracil, an analog of thymine.
  • dihydrofolate reductase is inhibited by methotrexate, a folic acid analog. Limits synthesis of thymidylate. Used in treatment of some cancers and psoriasis.
73
Q

Describe the pyrimidine salvage pathway.

A

free nitrogen base is added to PRPP.

74
Q

Difference between products of purine and pyrimidine catabolism.

A

In purine catabolism, ring remains intact. product (UA) is less soluble that products of pyrimidine catabolism.

In pyrimidine catabolism, ring is cleaved, and ammonium products are more soluble.

75
Q

Anticancer purine analogs?

A

thiopurines and deoxyadenosine derivatives

76
Q

Nucleic acids are degraded to nucleotides by ____

A

nucleases

77
Q

nucleotides are degraded to nucleosides + P by _____

A

nucleotidases

78
Q

nucleosides are degraded to ribose-1-phosphate and free base by _____

A

nucleoside phosphorylase

79
Q

purine bases are converted to form xanthine, and xanthine is degraded to uric acid by _____

A

xanthine oxidase

80
Q

what type of nitrogen is excreted by humans?

A

uric acid

81
Q

What enzyme converts adenosine to inosine?

A

adenosine deaminase

82
Q

ADA deficiency

A

adenosine deaminase deficiency:

–inhertied

  • blockage of DNA synthesis
  • high cellular concentrations of dATP with subsequent inhibition of ribonucleotide reductase and dNTP synthesis
  • results in severe combined imunodeficiency syndrome (SCIDS)
83
Q

What is hyperuricemia?

A

elevated levels of uric acid due to overproduction (too much purine breakdown) or underexcretion, leading to gout (uric acid crystals).

84
Q

Treatment for hyperuricemia?

A

Reduce concentration of uric acid:

  • use allopurinol, analog of hypoxanthine and competitive inhibitor of xanthine oxidase.
  • increases concentrations of hypoxanthine and xanthine, and decreases amount of uric acid
85
Q

Why is uric acid produced from xanthine in humans?

A

It is a scavenger of reactive oxygen species.

86
Q

Describe the catabolism of pyrimidines.

A
  1. nucleotide is broken down to nucleoside and then a free base
    2a. cytosine is deaminated to uracil. Uracil is degraded to alanine, CO2, and ammonium
    2b. thymine is degraded to aminoisobutyrate (used as meaure in urine of DNA turnover, as it is specific to thymine catabolism), CO2, and ammonium

Products are soluble and excreted

CORE Block 5 (4 decks)

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