Metabolism 11: Purine and Pyrimidine Nucleotide Metabolism

Question 1

Which bases are purines?

Answer 1

Adenine

Guanine

Question 2

Which bases are pyrimidines?

Answer 2

Cytosine
Urasil
Thymine

Question 3

Where do the atoms in the purine ring structure come from?

Answer 3

3 amino acids (glycine, glutamine, aspartate)
CO2
FH4 (tetrahydrofolate) derivative

Question 4

What is the precursor for purine biosynthesis and where does it come from?

Answer 4

Ribose-5-phosphate from the pentose phosphate pathway

Question 5

How is the purine ring built?

Answer 5

Built up atom by atom on top of ribose

Question 6

What is the first step in purine biosynthesis

Answer 6

Activation of R5P to get PRPP (Pyrophosphate from ATP)

Question 7

What is the second step in purine biosynthesis?

Answer 7

Formation of 5-phosphoribosylamine using the amino group of glutamine

Question 8

What enzyme catalyzes the second step in purine biosynthesis

Answer 8

Glutamine PRPP Amidotransferase

Question 9

What is the committed and major regulated step in purine biosynthesis

Answer 9

The 2nd step using glutamine PRPP amidotransferase to generate 5-phosphoribosylamine

Question 10

What is eventually formed in step 11 of the purine biosynthesis pathway?

Answer 10

Nucleotide IMP (inosinic acid) that is the precursor for both AMP and GMP

Question 11

Once we create AMP and GMP via purine biosynthesis, how do we get the di and tri phosphate derivatives?

Answer 11

Through phosphorylation -> ADP,GDP -> ATP,GTP

Question 12

How is the enzyme glutamine PRPP amidotransferase regulated?

Answer 12

+: PRPP (feed forward activation)

-: IMP, GMP, AMP (Negative feedback inhib)

Question 13

How are normal tissues and tumors different with regards to purine biosynthesis?

Answer 13

Tumors are highly dependent on purine biosynthesis to produce purine nucleotides for DNA/RNA synthesis

Normal tissue are less dependent on de novo synthesis and prefer recycling existing purine bases by a salvage pathway

Question 14

What is the idea of a drug inhibiting purine biosynthesis?

Answer 14

It will be more toxic to tumor cells than most normal cells due to their dependent on purine biosynthesis for DNA/RNA syntehsis

Question 15

What is 6-mercaptopurine?

Answer 15

Antitumor agent that is converted to a nucleotide and then inhibits enzymes in the purine biosynthetic pathway.

Used to treat acute lymphocytic leukemia

Question 16

What are the sources of the atoms in the pyrimidine ring structure?

Answer 16

Glutamine, aspartate, CO2

Question 17

What is the regulated step in pyrimidine biosynthesis?

Answer 17

Carbamoyl Phosphate Synthetase II

Question 18

How is the pyrimidine nucleotide formed?

Answer 18

Pyrimidine ring structure formed first and then added to ribose-5-phosphate

Question 19

What is the precursor for synthesis of all the other pyrimidine nucleotides?

Answer 19

UMP

Question 20

What is Leflunomide?

Answer 20

Immunosuppressive drug for treating rheumatoid arthritis.

Blocks pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase

Question 21

How is dTMP synthesized?

Answer 21

From dUMP and N5N10 methylene tetrahydrofolate using the enzyme thymidylate synthase

Question 22

What enzyme catalyzes the conversion of dUMP to dTMP?

Answer 22

Thymidylate Synthase

Question 23

What is a byproduct of dTMP synthesis that is toxic?

Answer 23

dihydrofolate: it is toxic and must be converted back to tetrahydrofolate by dihydrofolate reductase for use again in purine/pyrimidine biosynthesis

Question 24

What enzyme converts dihydrofolate back to tetrahydrofolate?

Answer 24

dihydrofolate reductase

Question 25

What is methotrexate?

Answer 25

Antitumor drug that acts as a Competitive inhibitor of dihydrofolate reductase that causes a buildup of the toxic byproduct dihydrofolate leading to tetrahydrofolate deficiency in cells

Question 26

What is 5-fluorouracil?

Answer 26

Antitumor drug that is converted to f-dUMP and acts as a pseudosubstrate to covalently bind and inhibit thymidylate synthase

Question 27

What does ribonucleotide reductase do?

Answer 27

Acts on ADP, GDP, CDP, or UDP to form the deoxyribonucleoside forms (dADP, dGDP, dCDP, dUDP) by replacing 2' OH group with H

Question 28

What cofactor is needed for ribonucleotide reductase

Answer 28

Thioredoxin

Question 29

What phase of the cell cycle does DNA synthesis occur?

Answer 29

S Phase

Question 30

When do concentrations of the deoxyribonucleotides rise?

Answer 30

During S Phase

Question 31

When do the enzymes of purine/pyrimidine biosynthesis increase?

Answer 31

Late G1/Early S1 phases

Question 32

Which enzymes increase in levels during late G1 Early S phase and correlate with tumor growth rate?

Answer 32

Ribonucleotide Reductase | Thymidilate Synthase

Question 33

What degrades DNA/RNA from diet and mRNA in cells to bases?

Answer 33

Nucleases ->nucleotidases ->nucleosidephosphorylases -> Bases (uracil, thymine, guanine, hypoxanthine)

Question 34

What happens to most free purine bases produced in cell from the degradation of mRNA?

Answer 34

90% are reused rather than degraded

Question 35

What is the salvage pathway?

Answer 35

pathway used to reutilize bases instead of having them degraded

Question 36

What causes Lesch-Nyhan Syndrome?

Answer 36

Deficiency in HGPRTase leading to neurological problems and gout

Question 37

What does the HGPRTase enzyme do?

Answer 37

Convert hypoxanthine and guanine to IMP and GMP using PRPP (Activated form of R5P)

Question 38

10% of purine base formed from mRNA catabolism forms what?

Answer 38

Uric Acid

Question 39

What is uric acid?

Answer 39

Final product of purine degradation that is excreted

Question 40

What does xanthine oxidase do?

Answer 40

Convert hypoxanthine and xanthine to uric acid

Question 41

What is the predominant form of uric acid in blood pH?

Answer 41

Urate

Question 42

What is the predominant form of uric acid in urine pH?

Answer 42

Uric Acid

Question 43

Which is more soluble urate or uric acid?

Answer 43

Urate

Question 44

How does gout occur?

Answer 44

Due to overproduction or underexcretion of uric acid

Question 45

What is hyperuricemia?

Answer 45

Elevated urate in blood. Can lead to deposition of sodium urate crystals in joints and cause painful inflammatory response

Question 46

What is hyperuricosuria?

Answer 46

Elevated uric acid in urine. Can lead to deposition of uric acid stones in kidney

Question 47

What is allopurinol and what does it treat?

Answer 47

Treats gout by inhibiting xanthine oxidase Inhibits formation of xanthing from hypoxanthine and uric acid from xanthine This reduces urate and uric acid levels in blood and urin