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SFM Exam 2 > Nucleotide Metabolism > Flashcards

Nucleotide Metabolism Flashcards

1
Q

Nucleosides consist of …

A

nitrogenous base + sugar (ribose or deoxyribose)

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2
Q

Nucleotides consist of …

A

nitrogenous base + sugar + phosphate

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3
Q

What are the 3 Pyrimidines?

A
  • Cytosine (C)
  • Thymine (T)
  • Uracil (U)
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4
Q

How many rings do Pyrimidines have?

A

1

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5
Q

How many rings do Purines have?

A

2

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6
Q

What are the 2 Purines?

A
  • Adenine (A)

- Guanine (G)

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7
Q

What are the two pathways that can be used to produce purine nucleotides?

A
  • De Novo Synthesis (occurs in liver, cytosol)

- Salvage Pathway (occurs in organelles)

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8
Q

What does De Novo Synthesis of Purines involve?

A

formation of purine base on ribose 5-phosphate (from PPP)

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9
Q

What does Salvage Pathway of Purines involve?

A

Addition of ribose 5-phosphate to pre-formed base

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10
Q

What does De Novo synthesis of Pyrimidines involve?

A

formation of pyrimidine ring structure followed by addition of ribose phosphate

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11
Q

Where does De Novo synthesis of Pyrimidines occur?

A
  • Liver
  • Cytosol
  • Mitochondria
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12
Q

What does Salvage Pathway of Pyrimidines involve?

A

formation of pyrimidine nucleotides from pyrimidine bases in RNA/DNA

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13
Q

What happens in Phase I of Purine Synthesis?

A

Activation of ribose 5-phosphate

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14
Q

What happens in Phase II of Purine Synthesis?

A

Conversion of PRPP (activated sugar) into phosphoribosylamine – RATE LIMITING STEP

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15
Q

What happens in Phase III of Purine Synthesis?

A

Construction of inosine monophosphate branch point purine ring (nitrogenous base)

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16
Q

What happens in Phase IV of Purine Synthesis?

A

Conversion of IMP into adenosine and guanosine (deoxy) nucleotides

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17
Q

What is the rate limiting step/enzyme of Purine Synthesis?

A

Glutamine Phosphoribosyl Pyrophosphate Amidotransferase (PRPP -> PRA)

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18
Q

What activates Glutamine Phosphoribosyl Pyrophosphate Amidotransferase?

A

PRPP

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19
Q

What inhibits Glutamine Phosphoribosyl Pyrophosphate Amidotransferase?

A

Purine nucleotides (GMP, AMP, IMP)

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20
Q

What activates PRPP Synthetase?

A

Pi

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21
Q

What inhibits PRPP Synthetase?

A

Purine nucleotides (GMP, AMP, IMP)

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22
Q

What inhibits the 9 step conversion of PRA to IMP?

A

Methotrexate

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23
Q

How many ATP are used in 9 step process to reach IMP product?

A

4

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24
Q

What inhibits Adenylosuccinate Synthetase?

A

AMP

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25
Q

What inbibits IMP Dehydrogenase?

A

GMP

26
Q

AMP synthesis is stimulated by __

A

GMP

27
Q

GMP synthesis is stimulated by __

A

AMP

28
Q

What happens in Phase I of Pyrimidine synthesis?

A

fabrication of pyrimidine ring as orotate

29
Q

What happens in Phase II of Pyrimidine synthesis?

A

attachment of orotate to PRPP to generate uridine monophosphate which is the branch point in pyrimidine synthesis

30
Q

What happens in Phase III of Pyrimidine synthesis?

A

conversion of UMP to CTP and dTMP

31
Q

What is the rate limiting step/enzyme of Pyrimidine synthesis?

A

Carbamoyl Phosphate Synthetase II

32
Q

Carbamoyl Phosphate Synthetase II is found only in the ___

A

Cytosol

33
Q

What activates Carbamoyl Phosphate Synthetase II?

A

PRPP

34
Q

What inhibits Carbamoyl Phosphate Synthetase II?

A

UTP

35
Q

What inhibits Thymidylate Synthase?

A

5-Fluorouracil

36
Q

What is the significance of the dUDP loop?

A

dUTPase keeps dUTP low to prevent incorporating into DNA

37
Q

___ bridges to thymidine production

A

dUMP

38
Q

How many ATP are required to generate the branch point nucleotide of Purine synthesis?

A

4 ATP to generate IMP

39
Q

How many ATP are required to generate the branch point nucleotide of Pyrimidine synthesis?

A

3 ATP to generate UMP

40
Q

Where does Purine Synthesis occur in the cell?

A

Cytosol

41
Q

Where does Pyrimidine Synthesis occur in the cell?

A

Cytosol and Mitochondria

42
Q

General steps of Purine Synthesis

A

uses an activated ribose platform (PRPP) on which tje base is constructed

43
Q

General steps of Pyrimidine Synthesis

A

generates the base independently of ribose; the base is attached to PRPP late in synthesis

44
Q

Feedback inhibition of Pruine Synthesis

A

accumulation of the end-product inhibits its own synthesis (ex. formation of AMP/GMP inhibits the formation of PRPP, phosphoribosyl amine, IMP)

45
Q

What are the 4 drugs that impact purine/pyrimidine synthesis?

A
  • Methotrexate
  • Fluorouracil
  • Sulfa Drugs
  • Acyclovir
46
Q

Methotrexate

A
  • target pathway: pyrimidine synthesis
  • target enzyme: Dihydrofolate Reductase (inhibition of this enzyme prevents oxidation of NADPH)
  • DHFR converts dietary form of folate into biologically active form in the liver
  • used to treat cancer
  • inhibition disrupts DNA replication in rapidly dividing cancer cells
  • leads to decreased formation of N-MTHF which means it can’t be converted to N10-fTHF and used in the synthesis of IMP
47
Q

Fluorouracil

A
  • target pathway: purine synthesis
  • target enzyme: Thymidylate Synthase (inhibition of this essentially stops DNA synthesis, normally methylates dUMP to dTMP)
  • used to treat cancer
  • injected to treat colon, esophageal, breast, cervical pancreatic cancers
  • topically used to treat warts, actinic keratoses, and basal cell carcinoma
  • works by triggering cell death in rapidly dividing cancer cells
48
Q

Sufla Drugs

A
  • antibacterial agents
  • look chemically similar to PABA molecule so competitively inhibit the bacteria specific enzyme Dihydropteroate Sythase to block synthesis of bacterial DNA
  • selectively disrupts DNA replication and protein synthesis in bacteria
  • frequently used to treat bladder and urinary tract infections
49
Q

Acyclovir

A
  • competitively binds to the enzyme Thymidine Kinase (normally phosphorylates the nucleotide deoxythymidine to generate dTMP)
  • preferential interaction of Thymidine Kinase with this drug results in formation of tri-phosphate version of drug that incorporates into rapidly dividing viral cells DNA; drug incorporation in DNA inhibits viral DNA Polymerase which terminates DNA replication in viral cell
  • used to help heal sores related to chicken pox, shingles and HPV/HSV
50
Q

Removal of ribose from guanosine and inosine produces __ and ___

A
  • Guaninine

- Hypoxanthine

51
Q

Severe Combined Immunodeficiency

A
  • BUBBLE BOY
  • problem with purine catabolism
  • fatal genetic disorder in which both T and B Cells of adaptive immunity are compromised
  • often males b/c most common form is X-linked
  • sxs: failure to thrive, chronic diarrhea, thrush, recurrent/severe/persistent infections
  • most common form due to mutations in the receptors shared by ILs involved in development and differentiation of B and T cells
  • ADA deficiency is second most common form; leads to increase in adenosine and decrease in inosine -> phosphorylation of AMP to ADP to ATP, increased ATP means downreg of production of other deoxy nucleotides which eventually leads to impaired DNA synthesis
52
Q

Gout

A
  • problem with purine catabolism
  • diagnostic marker: serum uric acid levels
  • characterized as high levels of uric acid in the blood
  • primary or secondary hyperuricemia
  • episodes triggered by diets rich in purines along with alcohol, meat and seafood
  • treatment involves reducing amount of granulocytes to affected areas, allopurinal that inhibits xanthine oxidase (leads to inhibition of uric acid formation)
53
Q

Secondary Hyperuricemia

A
  • under-excretion of uric acid

- results in sodium urate deposits in the kidneys

54
Q

Primary Hyperuricemia

A
  • overproduction of uric acid

- results in painful deposits of sodium urate in the proximal joints of extremities

55
Q

Which pathway is dominant for purine synthesis?

A

Salvage Pathways

56
Q

Lesch-Nyhan Syndrome

A
  • results from defects in HGPRT (hypoxanthine-guanine phosphoribosyltransferase, generates GMP or IMP)
  • affected pathway: purine salvage
  • rare form of hyperuricemia (high uric acid level in blood)
  • leads to gout, urate kidney stones, poor muscle control, severe cognitive impairment, tendency to self mutilate
57
Q

What do defects in salvage pathway lead to?

A

(1) excess guanine and hypoxanthine not used in pathway are shunted to form 6x the normal levels of uric acid
(2) purine biosynthesis proceeds at levels 200x normal. PRPP which is not used in salvage pathway is available for additional purine biosynthesis and allosterically activates the next enzyme in purine biosynthesis. Additional PRPP leading to more PRA has mass action effect on additional synthesis for more purines

58
Q

Severity of Lesch-Nyhan depends on ___ activity

A

HGPRT

59
Q

<1.5% normal HGPRT activity

A
  • Lesch-Nyhan syndrome present

- additional neurological problems including spastic cerebral palsy, choreoathetosis, and self destructive biting

60
Q

> 8% normal HGPRT activity

A
  • Kelly-Seegmiller Syndrome
  • sxs: gout, kidney destruction
  • NO NEURO SXS

SFM Exam 2 (10 decks)

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