L33- Pyrimidine Metabolism

Question 1

The first step in pyrimidine synthesis is the synthesis of carbamoyl phosphate in the cytoplasm. What is the enzyme that catalyzes this step?

Answer 1

Carbamoyl phosphate synthetase II (CPSII); not to be confused with CPS I which is in the mitochondria and involved in the urea cycle!

Question 2

Which three enzymes are domains of the same protein that yields dihydroorotate?

Answer 2

CPS II, aspartate transcarbamoylase and dihydroorotase.

Question 3

Which enzyme oxidizes dihydroorotate to orotate?

Answer 3

Dihydroorotate dehydrogenase.

Question 4

What reaction is catalyzed by orotate phosphoribosyltransferase (OPRT)?

Answer 4

Condensation of orotate with PRPP to form orotidine-5-phosphate (OMP).

Question 5

Which enzyme generates UMP from OMP?

Answer 5

OMP decarboxylase.

Question 6

Deficiency of which enzyme(s) can lead to orotic aciduria?

Answer 6

The bifunctional protein that consists of both orotate phosphoribosyltransferase (OPRT) and OMP decarboxylase. Orotic aciduria can also be secondary to urea cycle enzyme deficiencies, like ornithine transcarbamylase (OTC) in particular.

Question 7

Which molecule is produced when the amide nitrogen from glutamine is transfered to the C4 of the UTP pyrimidine ring?

Answer 7

CTP.

Question 8

What class of enzyme is thought to be involved in pyrimidine synthesis via the salvage pathway?

Answer 8

The pyrimidine nucleoside kinases.

Question 9

What is the end product of the catabolism of uracil?

Answer 9

Beta-alanine.

Question 10

What is the end product of the catabolism of thymine?

Answer 10

Beta-aminoisobutyrate.

Question 11

True or False. Unlike purine catabolism, pyrimidine catabolism occurs in the liver, yields soluble end products, and the pyrimidine rings are opened.

Answer 11

True.

Question 12

Which enzyme converts ribonucleosides disphosphates into deoxyribonucleoside diphosphates?

Answer 12

Ribonucleotide reductase.

Question 13

What is the function of the small protein thioredoxin?

Answer 13

It is the electron donor in the reaction catalyzed by ribonucleotide reductase. In other words, it reduces ribonucleoside diphosphates to deoxyribonucleoside diphosphates.

Question 14

Which enzyme regenerates the reduced form of thioredoxin?

Answer 14

Thioredoxin reductase.

Question 15

What is the cofactor for the reaction catalyzed by thioredoxin reductase?

Answer 15

FAD.

Question 16

Which enzyme is inhibited by hydroxyurea?

Answer 16

Ribonucleotide reductase.

Question 17

What is the product of dUMP methylation?

Answer 17

TMP.

Question 18

Which enzyme methylates dUMP to form TMP?

Answer 18

Thymidylate synthase.

Question 19

What is the carbon donor in the methylation of dUMP to produce TMP?

Answer 19

N5, N10 - methylene tetrahydrofolate.

Question 20

Formation of TMP from dUMP oxidizes tetrahydrofolate to dihydrofolate. What enzyme regenerates tetrahydrofolate?

Answer 20

Dihydrofolate reductase.

Question 21

What is the main regulatory site of de novo pyrimidine synthesis?

Answer 21

The carbamoyl phosphate synthetase II (CPS II) reaction.

Question 22

What are the activators and inhibitors of carbamoyl phosphate synthetase (CPS II)?

Answer 22

CPS II is stimulated by PRPP and ATP, and inhibited by UTP.

Question 23

What are the activators and inhibitors of OMP-decarboxylase?

Answer 23

OMP-decarboxylase is inhibited by UMP and indirectly stimulated by PRPP.

Question 24

Which pyrimidine synthesis metabolite accumulates when OMP-decarboxylase is inhibited?

Answer 24

Orotate (not OMP). This is because orotate phosphoribosyltransferase (OPRT) and OMP-decarboxylase are located on the same polypeptide.

Question 25

Orotic aciduria can be treated by administration of which nucleoside?

Answer 25

Uridine.

Question 26

How do ATP and dATP regulate ribonucleotide reductase?

Answer 26

Ribonucleotide reductase is activated by ATP and inhibited by dATP.

Question 27

Methotrexate is an analogue of ______ and inactivates ______.

Answer 27

Folic acid, dihydrofolate reductase.

Question 28

Methotrexate inhibits the production of which nucleotide?

Answer 28

TMP.

Question 29

Which drug is particularly effective against childhood leukemias?

Answer 29

Methotrexate.

Question 30

5-Fluorodeoxyuridine is an analogue of _____ that binds to the enzyme _____, thereby blocking _____ synthesis.

Answer 30

dUMP, thymidylate synthetase, TMP.