Nucleotide Metabolism Flashcards

1
Q

Purine bases

A
  • Adenine
  • Guanine
  • Hypoxanthine
  • Xanthine
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2
Q

Pyrimidine bases

A
  • Uracil
  • Cytosine
  • Thymine
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3
Q

PRPP Synthesis

A
  • From ribose-5-phosphate and ATP

- Catalyzed by PRPP Synthetase

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4
Q

Sources of ribose-5-phosphate

A
  • Glucose metab, pentose phosphate shunt

- Nucleoside degradation creates R1P which can be converted

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5
Q

PRPP is required for:

A
  • Purine and pyrimidine nucleotide de novo synthesis
  • Salvage pathways for purine nucleotides
  • Biosynthesis of NAD and FAD
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6
Q

Synthesis of purine nucleotides

A
  • Purine ring built on PRPP

- Precursors are glutamine, glycine, CO2, aspartate, and two 1 carbon fragments from one-carbon folate pool (THF)

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7
Q

Sulfonamides

A
  • Block the biosynthesis of folate by bacteria

- Blocks two steps in the production of IMP that require folate

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8
Q

Components of IMP nucleotide ring

A

-Glutamine, glycine, CO2, aspartate, two one carbon fragments from the one-carbon folate pool

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9
Q

Azaserine

A
  • Analog of glutamine that blocks amide transfer from glutamine
  • Interferes with two steps in IMP production that require glutamine transfer reactions
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10
Q

Energy cost of making IMP

A

-Six high energy phosphate bonds

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11
Q

Formation of AMP from IMP

A
  • Adenylosuccinate formed by addition of aspartate to IMP
  • Fumarate cleaved to yield AMP
  • GTP cleaved in the process
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12
Q

Formation of GMP from IMP

A
  • XMP formed by oxidation of IMP
  • Amino group from glutamine added to form GMP
  • ATP cleaved in the process
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13
Q

HGPRT

A
  • Catalyzes formation of NTs from hypoxanthine or guanine (forms IMP and GMP respectively)
  • Salvage pathway
  • Uses PRPP
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14
Q

APRT

A
  • Catalyzes formation of AMP from adenosine
  • Salvage pathway
  • Uses PRPP
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15
Q

Nucleoside kinase

A
  • Salvage pathway only for adenosine

- Forms AMP and ADP using ATP

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16
Q

Synthesis of pyrimidine nucleotides

A
  • NOT built on PRPP. Synthesized first and then reacts with PRPP to form nucleotide
  • Precursors are carbamoylphosphate and aspartate
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17
Q

Formation of carbamoylphosphate in the production of UMP

A

-Carbamoylphosphate synthesized in the cytosol from glutamine and CO2. Also synthesized in liver as an intermediate in urea synthesis (takes place in mitochondria with a different enzyme).

18
Q

Orotic aciduria

A
  • Genetic disorder of pyrimidine biosythnesis (the first enzyme)
  • Orotic acid accumulates in blood and excreted in urine.
  • Alleviated by feeding of uridine or cytidine: supplies the body with needed pyrimidine
19
Q

Pyrimidine synthesis

A
  • Conversion of UMP to UTP Two steps
    1. UMP Kinase
    2. Nucleoside diphosphate kinase
  • Amino group from glutamine then donated to UTP to form CTP (activated by GTP)
20
Q

Uracil salvage pathway

A
  • Uracil converted to UMP by two sequential reactions
    1. Uridine phosphorylase: Uracil + Ribose-1-phospate –> Uridine + Pi
    2. Uridine kinase: Uridine + ATP –> UMP + ADP
21
Q

Cytidine salvage pathway

A

-Can also be phosphorylated by uridine kinase

22
Q

Enzymes inhibited by azaserine

A
  • Any that use glutamine as an amino donor
  • CPSII
  • CTP synthase
  • FGAR aminotransferase
  • GMP synthase
  • PRPP aminotransferase
  • Asparagine synthase
23
Q

When are deoxyribonucleotides sythesized?

A

-When cells are actively dividing and in S phase

24
Q

Formation of deoxynucleotides

A
  • Formed from reduction of ribonucleoside diphosphates (ONLY)
  • Reduction catalyzed by ribonucleotide reductase
25
Q

Products of ribonucleotide reductase

A

-dCDP, dADP, dGDP, dUDP

26
Q

Fate of dUDP

A
  • Not incorporated into DNA so dephosphorylated to dUMP state
  • dTMP formed from dUMP via thymidylate synthase
27
Q

Thymidylate synthase reaction

A
  • Forms dTMP from dUMP

- Methylene group from N5N10 methylenetetrahydrofolate transferred and reduced to a methyl group

28
Q

Regeneration of THF

A
  • Via dihydrofolate reductase
  • Requires NADPH
  • Only made by cells in S phase
29
Q

5-Fluorouracil

A
  • Anticancer agent
  • Converts to F-UMP in cells
  • Converted to F-dUMP which is the critical form!
  • F-dUMP interacts with thymidylate synthase and N5N10 methylenetetrahydrofolate
  • Transfer of a methylene group to pyrimidine ring is blocked by fluorine so thymidylate synthase is trapped and can’t synthesize dTMP
30
Q

Methotrexate

A
  • Anticancer agent
  • Analog of folic acid
  • Inhibits dihydrofolate reductase
  • Regeneration of THF is blocked and synthesis of dTMP is inhibited
31
Q

Salvage pathway for synthesis of thymine deoxyribonucleotides

A
  • Thymine phosphorylase converts thymine to thymidine

- Thymidine kinase converts thymidine to dTMP

32
Q

Nucleotide degradation via dephosphorylation

A
  • Nucleotidases remove 5’ phosphates from ribo and deoxyribo nucleotides converting them to nucleosides
  • AMP deaminated to IMP and then hydrolyzed to inosine or hydrolyzed to adenosine and then deaminated to inosine
  • GMP hydrolyzed to guanosine
  • CMP deaminated to UMP then hydrolyzed to uridine or hydrolyzed to cytidine then deaminated to uridine
  • UMP hydrolyzed to uridine
33
Q

Nucleotide degradation via phosphorolysis

A
  • Nucleoside phosphorylases
  • A bond is cleaved by adding Pi
  • Form free base and R1P or dR1P
34
Q

Purine degradation

A
  • Final product is uric acid
  • Hypoxanthine oxidized to xanthine by xanthine oxidase
  • Guanine deaminated to xanthine
  • Xanthine oxidized to uric acid by xanthine oxidase–O2 required and superoxide formed
35
Q

Components of purine degradation

A
  • Dephosphorylation
  • Deamination
  • Separation of base from ribose
  • Oxidation to uric acid
36
Q

Degradation of pyrimidines

A
  • Final produces B-alanine (from uracil) and B-aminoisobutyrate from thymine
  • Undergo same components as purine degradation
37
Q

Cause of gout

A
  • Precipitation of sodium urate crystals in joints and kidneys
  • PRPP synthetase may be too active
  • Partial deficiency of HGPRT leads to increased PRPP which leads to increased purine synthesis
38
Q

Treatment of gout

A
  • Allopurinol
  • Blocks production of uric acid
  • Oxidized by xanthine oxidase to oxypurinol which binds tightly to xanthine oxidase inhibiting its function
  • Colchine may also be used
39
Q

Allopurinol in cancer treatment

A

-Can help deal with the large quantities of nucleotides released from killed cancer cells

40
Q

Lesch-nyhan syndrome

A
  • Hereditary X linked recessive condition
  • Severe or complete deficiency of HGPRT
  • Increased synthesis of purines
  • Hyperuricemia, gout, neurological symptoms (not sure why)
  • Allopurinol won’t relieve neurological symptoms
41
Q

ADA deficiency (SCID)

A
  • Adenosine deaminase deficiency
  • deoxyadenosine and adenosine are abundant because cannot be degraded to inosine and deoxyinosine
  • Inhibits ribonucleotide reductase which inhibits DNA synthesis
  • White blood cells cannot proliferate