Pyrimidine Metabolism

Question 1

The goal of pyrimidine synthesis is to create

Answer 1

CMP, UMP, TMP

Question 2

How is pyrimidine construction different than purine construction?

Answer 2

In pyrimidine synthesis, base is made first and then ribose sugar (PRPP) gets added.

Question 3

What two phosphorylation steps require ATP during carbamoyl phosphate synthesis?

Answer 3

1. phosphorylation of bicarbonate

2. phosphorylation of carbamic acid

Question 4

Describe the Structure of Carbamoyl Phosphate Synthetase II

Answer 4

1. dimer with one small subunit and one large subunit
2. total of 3 active sites
3. small subunit hydrolyzes glutamine to amine
4. large subunit has 2 active sites
   - bicarbonate gets phosphorylated to carbamic acid
   - carbamic acid gets phosphorylated to carbamoyl phosphate

Question 5

What is the rate-limiting enzyme in pyrimidine synthesis?

Answer 5

carbamoyl phosphate synthetase II

Question 6

what is the structure of pyrimidine ring?

Answer 6

• 6 membered ring (2 nitrogens, 4 carbons)

- Half of ring comes from Carbamoyl phosphate, other half of ring comes from aspartate

Question 7

What is the disorder that is caused by a defect in orotidylate decarboxylase leading to build up of orotic acid, stunted growth, anemia, and decreased pyrimidine production?

Answer 7

Orotic Aciduria

Question 8

What enzyme replenishes tetrahydrofolate?

Answer 8

dihydrofolate reductase

Question 9

What is 1 carbon carrier that donates a methyl group to form TMP?

Answer 9

tetrahydrofolate (N5, N10-methylenetetrahydrofolate)

Question 10

Where is THF (tetrahydrofolate) acquired?

Answer 10

from the diet (folate) or intestinal flora

Question 11

What is the function of acyclovir?

Answer 11

Acyclovir is an anti-herpes antiviral that inhibits herpes viral replication by being converted into acyclovir triphosphate by viral thymidine kinase. It gets incorporate into DNA and acts as a chain terminator.

• acyclovir inhibits mammalian DNA polymerase activity when incorporated into DNA.

Question 12

What supplies electrons for ribonucleotide reductase to carry out conversion of NDPs to dNDPs?

Answer 12

thioredoxin sulfate groups

Question 13

What replenishes electrons of reduced thioredoxin groups?

Answer 13

NADPH

Question 14

Describe two regulatory sites of ribonucleotide reductase

Answer 14

1. activity site: activated by ATP; inhibited by dATP

2. specificity site: cross-regulation occurs where high levels of one dNTP activates/inhibits synthesis of another.

Question 15

What is the drug that acts as an anti-tumor drug by being converted to fluorodeoxyuridylate by thymidylate synthase to inhibit the enzyme from forming dTMP?

Answer 15

fluorouracil (5-FU)

Question 16

What are the drugs that mimic dihydrofolate (DHF) bind and inhibit dihydrofolate reductase to block dTMP synthesis?

Answer 16

methotrexate & aminopterin

Question 17

What is the disorder due to a defect in adenosine deaminase causing an accumulation of dAMP –> dATP that can inhibit ribonucleotide reductase and DNA synthesis?

Answer 17

SCID