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FHB Exam 3 > Metabolism: Purines and Pyrimidines > Flashcards

Metabolism: Purines and Pyrimidines Flashcards

1
Q

What is the precursor for purine biosynthesis? What is its origin?

A

ribose-5-phosphate

PPP

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2
Q

What are the first 2 steps in purine synthesis?

A
  1. R5P => PRPP (PP comes from ATP)

2. => 5-phosphoribosylamine via glutamine PRPP amidotransferase (amino group added to PRPP comes from glutamine)

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3
Q

What is the first committed and major regulated step of purine biosynthesis?

A

PRPP + glutamine amino group => 5-phosphoribosylamine

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4
Q

What is the end-product of purine biosynthesis?

A

IMP (inosinic acid) => AMP, GMP

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5
Q

Where does the skeleton for purine biosynthesis originate?

A

3 AAs - asp, glutamine, gly
THF derivatives
CO2

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6
Q

What is the intermediate of the IMP => AMP reaction?

A

adenylosuccinic acid

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7
Q

What is the intermediate of the IMP => GMP reaction?

A

xanthylic acid (XMP)

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8
Q

List activators of the PRPP => 5-phosphoribosylamine reaction.

A

PRPP

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9
Q

List inhibitors of the PRPP => 5-phosphoribosylamine reaction.

A

IMP
AMP
GMP

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10
Q

List regulators of the IMP => AMP rxn.

A

AMP = inhibition

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11
Q

List regulators of the IMP => GMP rxn.

A

GMP = inhibition

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12
Q

What is the difference between purine synthesis in normal cells vs. tumor cells? Why is this important in combatting tumors.

A

in normal cells, most purines are just recycled and reused.
in tumor cells, de novo biosynthesis is promoted.
Thus, agents that prevent de novo purine synthesis will affect tumor cells more selectively than normal cells.

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13
Q

Describe the mechanism of 6-mercaptopurine.

A
  • used to treat acute lymphocytic leukemia (ALL) and other cancers
  • converted to a nucleotide
  • inhibits purine biosynthetic enzymes (including glutamine PRPP amidotransferase)
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14
Q

Describe the first step in pyrimidine synthesis.

A

glutamine + CO2 + ATP => glutamate + carbamoyl phosphate

via: carbamoyl phosphate synthetase II (recall: urea cycle)

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15
Q

What is different about the synthesis of purines vs pyrimidines?

A

purines = ribose-5-phosphate is already formed…add on purine base one carbon at a time

pyrimidines = base is formed first and then PRPP is added to the base as an activated form of R5P

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16
Q

What is the end product of pyrimidine synthesis?

A

UMP => UTP, CTP, TTP

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17
Q

Describe the function of leflunomide.

A
  • immunosuppressant used to treat rheumatoid arthritis
  • blocks pyrimidine biosynthesis
  • works by blocking dihydroorotate dehydrogenase
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18
Q

What is the function of dihydroorotate dehydrogenase?

A

takes NAD => NADH

L-hydroorotic acid => orotic acid

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19
Q

Describe the reaction that forms dTMP.

A
  1. dUMP => dTMP via thymidylate synthase
  2. N5,N10-methylene-THF => DHF
  3. DHF => THF via DHF reductase and NADPH
20
Q

How does 5-fluorouracil work?

A

converted to dUMP
binds to thymidylate synthase and inhibits the enzyme
prevents formation of dTMP

21
Q

Why is DHF converted back to THF?

A

DHF is actually toxic

to be used in purine and deoxythymidylate biosynthesis

22
Q

How does methotrexate work?

A
  • inhibits DHF => THF by competitive inhibition of DHF reductase
  • causes intracellular THF deficiency
  • prevents purine and deoxythymidylate biosynthesis
23
Q

How do you form deoxyribose?

A
  • enzyme: ribonucleotide reductase
  • takes ribose NTPs => deoxyNTPs
  • cofactor = thioredoxin
  • replaces 2’OH to H
24
Q

When does DNA synthesis occur?

A

S phase

25
Q

When are purine/pyrimidine biosynthesis enzymes synthesized?

A

late G1/early S

26
Q

What is the relationship between purine/pyrimidine biosynthesis enzymes and tumor growth rate?

A

enzyme levels increased

27
Q

Describe the steps and enzymes involved in DNA/RNA degradation back to the purines/pyrimidine bases.

A
  1. DNA/RNA => nucleoTides (via nucleases)
  2. nucleoTides => nucleoSides (via nucleotidases)
  3. nucleoSides => bases (via nucleoside phosphorylase)
28
Q

Which bases are the end products of DNA/RNA degradation?

A

U
T
G
hypoxanthine (from A)

29
Q

What enzyme is involved in the salvage pathway?

A

HGPRTase

30
Q

Define the salvage pathway.

A

90% of free PURINE bases in the cell from mRNA degradation are reutilized

31
Q

Describe the reaction involved in the salvage pathway.

A

hypoxanthine + PRPP => IMP

guanine + PRPP => GMP

32
Q

Describe Lesch-Nylan syndrome.

A
  • HGPRTase deficiency
  • neurological problems - spasticity, mental retardation, compulsive self-mutilation
  • affects only males
  • comanifests with gout
33
Q

What is the final product of purine degradation?

A

uric acid

34
Q

Describe the steps leading to uric acid synthesis.

A
  1. G + hypoX => xanthine (via xanthine oxidase)

2. xanthine => uric acid (via xanthine oxidase)

35
Q

What is the predominant form of uric acid in the blood? in the urine? Why is this different?

A

blood - urate
urine - uric acid
uric acid is less soluble than urate; below pH 5.8 = uric acid; above pH 5.8 = urate

36
Q

Describe hyperuricemia.

A
  • elevated uric acid in blood
  • deposition of sodium urate crystals in joints
  • acute inflammatory response (tophi)
  • gout
37
Q

Describe hyperuricosuria.

A
  • elevated uric acid in urine

- deposition of uric acid stones in the kidney

38
Q

Describe the mechanism of allopurinol.

A
  • gout treatment
  • xanthase oxidase inhibitor
  • block formation of uric acid
39
Q

What is the function of THF?

A
  • carries Carbon

- derivative of folate (required in diet; B9)

40
Q

Which THF derivative is used in purine synthesis?

A

N10-formyl-THF

41
Q

Which THF derivative is used in pyrimidine synthesis?

A

N5, N10-methylene-THF

only used for thymidylate

42
Q

What does a folic acid deficiency lead to?

A
  • megaloblastic anemia
  • immature RBCs can’t divide b/c can’t synthesize purines and pyrimidines
  • they have weak membranes that get destroyed
43
Q

What is the form of folic acid in the diet?

A

5-methyl-THF

44
Q

How is dietary folate converted to active folate? What cofactors and co-reactions are required?

A

5-methyl-THF => THF
via methylcobalamin (B12)
converts homocysteine to methionine

45
Q

What does a B12 deficiency lead to?

A
  • folate deficiency b/c can’t form THF

- megaloblastic anemia

46
Q

What kind of regulation is the purine rate limiting step under? (enzyme: glutamine PRPP amidotransferase)

A

allosteric negative feedback

47
Q

Where do the components of a pyrimidine come from?

A

glutamine
asp
CO2

FHB Exam 3 (23 decks)

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