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Hematology > 10.08.18 Nucleotide Metabolism > Flashcards

10.08.18 Nucleotide Metabolism Flashcards

1
Q

Adenine, Xanthine, Guanine, Hypoxanthine, Uric Acid, and Inosine are examples of what?

A

Purines

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2
Q

Cytosine, Thymine, and Uracil are examples of what?

A

Pyrimidines

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3
Q

What is a nucleoside made of?

A

Base+Sugar

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4
Q

What is nucleotide made of?

A

Base+Sugar+ Phosphate group

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5
Q

What is the difference between RNA and DNA?

A

-OH instead of -H at second carbon of sugar

RNA is less stable

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6
Q

What are the sources of nucleotides?

A
  1. Dietary
  2. De novo synth
  3. Salvage pathway
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7
Q

____ is the precursor to PRPP

A

Ribose 5-phosphate

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8
Q

an activated form of ribose that initiates synthesis

A

PRPP

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9
Q

common precursor to purine nucleotides and the branch point for the synthesis of different purines

A

IMP

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10
Q

Ribose 5-phosphate is derived from ___ via PPP or salvage pathway

A

Glucose

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11
Q

Pentose molecule that participates in synthesis and salvage of purines and pyrimidines

A

5-phosphoribosyl-1-pyrophosphate (PRPP)

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12
Q

What enzyme converts Ribose 5-phosphate + ATP –> PRPP

A

PRPP synthetase

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13
Q

What upregulates PRPP synthetase what downregulates it?

A

+: Ribose 5-phosphate, Pi (indicates low nt levels)

-: purine nt, ADP, GDP

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14
Q

X-linked disorder associated with severe nervous system abnormalities and decreases in PRPP synthetase activity

A

Arts Syndrome

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15
Q

What happens when PRPP synthetase activity reduces?

What happens when PRPP synthetase is increased?

A

Reduced purine levels; hypoxanthine absent from urine/uric acid is reduced in serum

Increased purine and gout

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16
Q

This enzyme action is irreversible (committed step) in purine synthesis

A

Glutamin phosphoribosyl amidotransferase

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17
Q

What reaction does glutamine phosphoribosyl amidotransferase catalyze?

A

Glutamine + PRPP –> 5-Phosphoribosylamine

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18
Q

What upregulates the commited in purine synth and what downregulates it?

A

+: PRPP

-: AMP, GMP, IMP, XMP (products)

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19
Q

What form of glutamine phosphoribosyl amidotransferase is active and which is inactive

A

Active= monomer

Inactive = dimer

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20
Q

How does glutamine affect the rate of glutamine phosphoribosyl amidotransferase?

A

Doesn’t

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21
Q

What does the rate of phosophorylrybosylamine depend on?

A

PRPP

Inhibited by products and has distinct binding sites

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22
Q

In how many steps is tetrahydrofolate the carbon donor in purine synth?

A

2

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23
Q

What rxns does dihydrofolate reductase (DHFR) carry out?

A
  1. Folate –> Dihydrofolate

2. Dihydrofolate –> THF

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24
Q

an anti-tumor drug that reduces the synthesis of THF by inhibiting DHFR

A

Methotrexate

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25
Q

What is the base for IMP?

A

Hypoxanthine

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26
Q

What is the precursor for both AMP and GMP?

A

IMP

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27
Q

AMP synthesis requires what for energy?

GMP synthesis requires what for energy?

What is this called?

A

GTP

ATP

Positive cross-regulation

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28
Q

What are AMP and GMP inhibitors of in their own synthesis?

A

AMP- adenylosuccinate synthetase

GMP- IMP dehydrogenase

29
Q

What does mycophenolic acid inhibit and what is it used in?

A

inhibits IMP dehydrogenase (GMP formation)

reduces lymphocyte proliferation and prevents graft rejection

30
Q

Other than mycophenolic acid, what is also used to inhibit IMP dehydrogenase?

A

RIbavarin

31
Q

What are the base specific kinases and what are the nonspecific kinases?

What do all these kinases require?

A

Base specific:

  • Adenylate kinase
  • Guanylate kinase

Nonspecific:
Nucleoside diphosphate kinase

ATP

32
Q

What is the basic pathway for purine degradation?

A

Nucleic acids –> Bases –> Uric acid

33
Q

What digest nucleic acids in the stomach?

A

Pepsin

34
Q

What is secreted by the pancreas to digest RNA/DNA into oligonucleotides?

A

RNAses and DNAses

35
Q

What degrades oligonucleotides to NMPs and dNMPs?

A

Phosphodiesterases

36
Q

What removes the phosphate groups from nucleotides to make nucleosides?

A

Nucleotidases (or phosphatases)

37
Q

What degrades nucleosides into free bases plus ribose/deoxyribose?

A

Nucleosidases

38
Q

How can hyperuricemia occur?

A
  1. Overproduction or uric acid

2. Limited excretion (90% of cases)

39
Q

Where does purine degradation occur?

A

Liver

40
Q

What does allopurinol do and what is used to treat?

A

Inhibits xantine oxidase

Treats Gout

41
Q

What are the 2 pathways AMP can become inosine?

A
  1. AMP – AMP deaminase –> IMP – 5’nucleotidase–> Inosine

2. AMP –5’nuclotidase–> Adenoside – Adenosine deaminase –> Inosine

42
Q

What does inhibition of adenosine deaminase lead to?

Why?

A

SCID

Used to make inosine and deoxyinosine; high levels of dATP inhibits ribonucleotide reductase which reduces DNA synthesis and low lymph count; high levels of deoxyadenosine levels may also be toxic

43
Q

What can an AMP deaminase deficiency lead to?

Why?

A
  1. Skeletal muscle myopathy
  2. Excercise-induced fatigue/cramps
  3. Asymptomatic

Function only in skeletal muscle and selective for only AMP (not dAMP)

44
Q

building nucleotides from bases/nucleosides (energetically advantageous)

A

Nucleotide salvage pathways

45
Q

What enzyme facilitates free base to nucleotide by adding phosphoribose using PRPP

What takes adenine to AMP?

What takes Guanine/hypoxanthine to IMP/GMP?

A

phosphoribosyl transferases

Adenine phosphoribosyltransferase (APRT)

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

46
Q

What enzyme converts a purine nucleoside into purine + ribose 1-phosphate?

A

Purine nucleoside phosphorylase

47
Q

What does a deficiency of purine nucleoside phosphorylase lead to?

A

T-cell immunodeficiency

48
Q

Decreased salvage of hypoxanthine and guanine and increased levels of PRPP

A

Lesch-Nyhan syndrome

49
Q

What are some factors that increase PRPP synthetase?

A
  1. Increased levels of PRPP
  2. Increased glutamine phosphoribosyl amidotransferase activity
  3. Increase in production of 5-phosphylribosyl 1-amine and nt
50
Q

What disease is from a deficiency of glucose-6-phosphatase?

A

Von Gierke disease

51
Q

How does Von Gierke disease contribute to gout uric acid overproduction?

A

G6P shunted to PPP pathway stimulates more nt synthesis

52
Q

X-linked recessive disorder with a deficiency of HGPRT

- neurological/behavioral abnormalities; gout

A

Lesch-Nyhan Syndrome

53
Q

What can you use to treat gout?

A

Acute gout: anti inflammatory agents, colchicine (for symptoms)

Chronic gout:
Allopurinol/Febuxostate- inhibit xanthine oxidase

Pegloticase/Rasburicase- convert uric acid to soluble allantoin

Probenecid, Lesinurad- promotes renal excretion of uric acid

54
Q

Why do cancer patients undergoing treatment have high levels of uric acid? What is this called?

A

Tumor Lysis Syndrome
- destruction of tumor cells/nucleic acid

Treat with allopurinol or Rasburicase

55
Q

What 2 AA and byproduct are needed for pyrimidine synthesis?

A
  1. Glutamine
  2. Aspartate
  3. CO2
56
Q

Which synthesis has ribose 5-phosphate backbone added later?

A

Pyrimidine

57
Q

What enzyme is used to convert glutamine and CO2 to carbamoyl phosphate?

A

Carbamoyl Phosphate Synthetase II (CPS II)

58
Q

What is carbamoyl phosphate inhibited by and activated by?

A
  • UTP

+ PRPP

59
Q

What enzyme converts carbamoyl phosphate and asparatate to carbamoyl aspartate?

A

Aspartate transcarbamoylase

60
Q

What enzyme converst dihydroorotate to orotate?

A

Dihydroorotate dehydrogenase

61
Q

Mutations in UMP Synthase results in poor growth, anemia, and high levels of orotic acid in urine due to lack of pyrimidines

A

Orotic Aciduria

62
Q

What is the committed step in pyrimidine synthesis?

A

CPS II

63
Q

What are the products of purine degradation

A

Malonyl CoA and Methylmalonyl CoA

64
Q

What cofactor is needed by ribonucleotide reductase?

A

Thioredoxin

65
Q

What is an anti-tumor compound that inhibits ribonucleotide reductase?

A

Hydroxyurea

66
Q

What drug permanently binds thymidylate synthase?

A

5-Fluorouracil

67
Q

What drug negatively inhibits PRPP amidotransferase and inhibits AMP and GMP production from IMP?

A

6-Mercaptopurine

68
Q

What drug inhibits dihydroorotate dehydrogenase?

A

Leflunomide

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