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FOS 2 > Nucleotide Metabolism > Flashcards

Nucleotide Metabolism Flashcards

1
Q

____ and ____ are activated precursors of RNA and DNA synthesis

A

Nucleotide triphosphates

deoxynucleotide triphosphates

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2
Q

Other than DNA synthesis, where else are nucleotides important in biological pathways?

A
  • Energy (ATP)
  • Activation of molecules in synthetic pathways (ATP, GTP)
  • Regulate protein function (phosphorylation, binding and hydrolysis i.e. Alpha subunit GPCRs)
  • Signal transduction (cAMP)
  • Synthesis of NAD, FAD and coenzyme A
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3
Q

If given the structure of a nucleotide, how would you determine if it is a purine or pyrimidine?

A

Purines are double ring structures

Pyrimidines are single ring structures

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4
Q

What is a nucleoside?

What is a nucleotide?

A

Nitrogenous base + pentose

Nitrogenous base + pentose + phosphate

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5
Q

What is the difference between a ribonucleotide and deoxyribonucleotide?

A

Ribo has 2’ OH, deoxy has a 2’ H

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6
Q

____ is supplied by folate (folic acid or vitamin B9)

A

Formate

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7
Q
A
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8
Q

____ is the cofactor needed for carboxylation in one-carbon metabolism.

A

Biotin

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9
Q

_____ is the cofactor needed for formylations in one cabron metabolism.

A

Folate

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10
Q

What is the most powerful methyl donor in one carbon metabolism?

A

SAM (S-denosyl-methionine)

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11
Q

The signs and symptoms of folate deficiency derive from a problem with ________ metabolism

A

Nucleotide

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12
Q

Where does the methyl group come from for the synthesis of SAM?

A

THF (Folate)

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13
Q

_____ accepts the methyl group from THF and transfers it to homocysteine

A

Vitamin B12

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14
Q

_____ is the major storage and transport form of THF.

A

N5-methyltetrahydrofolate

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15
Q

What happens to the following markers with a vitB12 deficiency?

1) THF levels
2) Homocysteine
3) Nucleotide synthesis?

A

1) Trapped as N-MTHF
2) Increased
3) Inhibited

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16
Q

___ links the pentose phosphate pathway and nucleotide metabolism.

A

Ribose

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17
Q

Enzymes that are synthetases use ____

A

ATP

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18
Q

____ catalyzes the conversion of ribose 5 phosphate to PRPP

A

PRPP Synthetase

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19
Q

What is PRPP?

A

A precursor to purine synthesis

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20
Q

What is the first committed step of purine biosynthesis?

A

Glutamine - PRPP - amidotransferase converts PRPP to another precursor for the pathway

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21
Q

What is the common intermediate from which Adenosine and Guanine are produced?

A

Inosinate

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22
Q

Which energy carrier is used for AMP synthesis?

A

GTP

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23
Q

Which energy carrier is used for GMP synthesis?

A

ATP

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24
Q

If ATP is higher than GTP, IMP will be used to make ____?

A

GMP

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25
Q

If ATP is lower than GTP, IMP will be used to make ____?

A

AMP

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26
Q

PRPP synthetase is inhibited by which compounds?

A

AMP

GMP

IMP

27
Q

Glutamine PRPP amidotransferase is inhibited by which compounds?

A

AMP

GMP

IMP

28
Q

If a patient presented with signs of both folate deficiency and vitamin B12 deficiency, how would you determine which one they had?

A

If vitamin B12, they would have build up of N-MTHF and Metylmalonyl coA b/c VitB12 is used in both of these pathways. THF is not related to lipid biosynthesis so there would be normal levels of methylmalonyl coA. This would point more toward a THF deficiency.

29
Q
A
30
Q

What is the enzyme that provides the carbamoyl phosphate for pyrimidine synthesis? Where is this enzyme located?

A

Carbamoyl synthetase 2 in the cytoplasm

31
Q
  • Where is most of the regulation in pyrimidine biosynthesis?
  • What enzyme is inhibited?
  • How is this enzyme regulated?
A
  • At the formation of carbamoyl phosphate in the cytoplasm
  • Carbamoyl synthetase 2
  • Feedback inhibition via UTP and CTP
  • Activation by ATP and PRPP
32
Q

In oroticaciduria type 1, defects are present in which 2 enzymes?

A

Orotate physphoribosyl transferase and orotidylate decarboxylase

33
Q

In type 2 oroticaciduria, which enzyme is defective?

A

Orotidylate decarboxylase

34
Q

How do patients with defects in pyrmidine biosynthesis present?

What compound is essential for these patients to receive via diet or supplementation?

A

Anemia that is not responsive to folate or vitamin B12

Uridine

35
Q
A
36
Q

Purines and pyrimidines are synthesized as ______

A

Ribonucleotides

37
Q

_______ catalyzes the reduction of the ribose moiety to deoxyribose

A

Ribonucleotide reductase

38
Q

Describe the structure of ribonucleotide reductase.

A

Consists of 2 x R1 subunits and 2 x R2 subunits. One R1 subunit is a regulatory site that contains the primary regulation site and the substrate specificity site. The other R1 subunit contains allosteric sites that are affected by deoxyribonucleotide levels.

39
Q

Explain the 2 ways in which ribonucleotide reductase is regulated.

A
  • Overall activity is regulated at primary regulation site by binding to ATP and dATP to control overall enzyme activity
  • Substrate specificity is regulated at the allosteric site by controlling substrate selection and this is regulated by relative levels of dNTPs formed
40
Q

dTMP is synthesized from either ____ or ____

A

dCTP or dUTP

41
Q

What enzyme prevents the incorporation of uracil into DNA?

A

dUTPase

42
Q

Explain why thymidylate synthesis supports the argument that DNA evolved from RNA.

A

Because we need thymidylate for our DNA but it is made from uridine

43
Q

What is the carbon source for conversion of dUMP to dTMP?

A

THF, which is oxidized in the process to 7,8 dihydrofolate

44
Q

What is fluorouracil and what does it target?

A

A suicide inhibitor of thymidylate synthase –> targeting cells that are undergoing DNA synthesis

45
Q

What enzyme is inhibited by methotrexate?

A

Dihydrofolate reductase (7,8 DHF –> THF). Inhibition of this enzyme results in a build up of 7,8 DHF which in turn inhibits the action of thymidylate synthetase and thus reduces production of dTMP

46
Q

What do sulfonamides target? How do they result in inhibition?

A

Folate synthesis in bacteria. They mimic the structure of PABA, which bacteria produce in their formation of folate. Because bacteria are obligate synthesizers of folate, when this pathway is blocked the drug selectively kills bacteria and not our cells because we can obtain folate from the diet where as bacteria cannot so they will die without a means of producing folate.

47
Q

What enzyme is inhibited by hydroxyurea?

A

Ribonucleotide reductase

48
Q

Deficiency in which enzyme results in Lesch-Nyhan syndrome?

A

Hypoxanthine-guanine phosphoribosyltrasferase (HGPRT)

49
Q

How is Lesch-Nyhan inherited?

A

X-linked

50
Q

How does a person with Lesch-Nyhan present?

A

Self mutilation behaviors

Mild intellectual disability

Hyperuricemia (high uric acid in blood, caused by purine breakdown and increased purine synthesis)

51
Q

What is the general scheme of salvage pathways?

A

Free nitrogenous bases are constanly being formed by catabolic pathways and those nitrogenous bases are difficult to make so the body recycles them by making nucleotides again. This is done by transfering ribose from PRPP to the nitrogenous base to make a nucleoside. This is different from de novo synthesis because the nitrogenous base is not being created but recycled as a whole unit onto PRPP.

52
Q

What metabolic pathway is associated with production of uric acid?

A

Purine degradation

53
Q

What 2 enzymes are important for purine salvage pathways?

A

Adenosine phosphoribosyltransferase (APRT)

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

54
Q

Primates cannot metabolize purine nucleotides past uric acid. What implication does this have clinically?

A

Primates will have high levels of uric acid b/c it cannot be metabolized further. As physiologic pH, uric acid is soluble but in the extremeties and avascular tissues (joints) where the temperature is lower the uric acid can crystallize and cause deposits that are painful.

55
Q

Hyperuricemia is most often associated with function of which organ system?

A

Kidneys

56
Q

What is the most common cause of hyperuricemia?

A

Increased resorption of urate from filtrate in kidneys

57
Q

What can result in increased levels of uric acid in the blood with regards to nucleotide metabolism?

A

Increased purine production and increased purine degradation

58
Q

What drug is used to treat gout? What are its 2 mechinisms of action?

A
  • Allopurinol
  • This is an analog of hypoxanthine and is a suicide inhibitor of xanthine oxidase, which converts xanthine to uric acid. This results in increased levels of more souble xanthine and hypoxanthine.
  • Allopurinol also lowers purine synthesis by being converted to allopurinol ribonucleotide that inhibits the first committed step of purine biosynthesis (glutamine - PRPP - amidotransferase)
59
Q
  • SCID can be caused by deficiency in which 2 enzymes invovled in nucleotide catabolism?
  • Why do deficiencies in these enzyme result in SCID?
A
  • 1) Adenosine deaminase deficiency –> most common cause of SCID
  • 2) Purine nucleoside phosphorylase (converts guanosine –> xanthine and adenosine –> hypoxanthine)
  • Patients accumulate purines and their T cells cannot metabolize purines so this is toxic to their immune cells
60
Q

Patients with SCID present with what in their blood?

A

Hypouricemia

61
Q

Unlike purines, pyrimidines synthesize the _____ first and the _____ is added later.

A

Ring

Ribose

62
Q

How is hypoxanthine formed?

A

Deamination of adenine

63
Q

Pyrimidine Catabolism

  • What are the end products of pyrimidine catabolism?
A
  • NH3, Urea and methyl-malonyl coA or propionyl coA which both then can be transformed into succinyl coA

FOS 2 (44 decks)

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