Purine and pyrimidine synthesis

Question 1

Which substrate in pyrimidine synthesis would be lowered due to 5-FU treatment?

Answer 1

dTMP

(Inhibitis thymidylate synthase = dUMP —> dTMP)

Question 1

What is required for de novo purine synthesis?

Answer 1

Aspartate, glutamine, glycine, THF

Question 2

Cofactor?

Orotic acid —> UMP

Answer 2

PRPP

Question 2

MOA of hydroxyurea?

Answer 2

Ribonucleotide reductase

(Inhibits UDP –> dUDP)

Question 2

Which substrate in purine synthesis would be lowered as a result of treatment with ribavirin or mycophenolate?

Answer 2

GMP

(Inhibit IMP dehydrogenase, so inhibit IMP —> GMP)

Question 3

Which substrate in pyrimidine synthesis would be higher with TMP, pyrimethamine, or MTX treatment? Lower?

Answer 3

dUMP higher

dTMP lower

(Inhibits DHFR = needed for reduction of DHF to THF to regenerate N⁵N¹⁰-methylene THF, the cofactor for dUMP —> dTMP reaction)

Question 4

Enzyme?

UDP —> dUDP

Answer 4

Ribonucleotide reductase

Question 6

Enzyme?

dUMP –> dTMP

Answer 6

Thymidylate synthase

Question 7

Which enzyme activates 6-MP?

Answer 7

HGPRT

Question 8

Which substrate in purine synthesis would be lower as a result of treatment with 6-mercaptopurine?

Answer 8

IMP

(Inhibits PRPP —> IMP)

Question 8

Which drug inhibits pyrimidine synthesis is bacteria specifically? Protozoa specifically?

Answer 8

Trimethoprim

Pyrimethamine

(DHFR inhibitors)

Question 9

MOA leflunomide?

Answer 9

Inhibits dihydroorate dehydrognase

(Inhibits carbamoyl phosphate —> orotic acid)

Question 10

Which drug would cause higher levels of PRPP?

Answer 10

6-mercaptopurine

(Inhibits PRPP —> IMP)

Question 11

Elevated DHF levels are indicative of treatment with which drugs?

Answer 11

Trimethoprim

Methotrexate

Pryrimethamine

Question 13

Steps in pyrimidine synthesis

Answer 13

Glutamine + CO2 —> Carbamoyl phosphate —> Orotic acid —> UMP —> UDP —> CTP + dUDP —> dUMP —> dTMP

Question 13

Which step in purine synthesis is inhibited by 6-mercaptopurine?

Answer 13

PRPP —> IMP

Question 15

Which step in pyrimidine synthesis is impaired in orotic aciduria?

Answer 15

Orotic acid —> UMP

Question 16

Which enzyme is needed for degradation of 6-MP?

Answer 16

TPMT and xanthine oxidase

(activated by HGPRT)

Question 17

Enzyme?

Ribose-5-P —> PRPP

Answer 17

PRPP synthetase

Question 19

Which drug would results in high levels of UDP?

Answer 19

Hydroxyurea

(Inhibits ribonucleotide reductase, so inhibits UDP —> dUDP)

Question 19

Enzyme?

DHF —> THF

Answer 19

Dihydrofolate reductase

Question 20

Which substrate in pyrimidine synthesis would be lowered as a result of hydroxyurea treatment?

Answer 20

dUDP

(Inhibits ribonucleotide reductase, so inhibits UDP —> dUDP)

Question 21

Which drugs would cause higher levels of IMP?

Answer 21

Ribavirin, mycophenolate

(Inhibit IMP dehydrogenase, so inhibits IMP —> GMP)

Question 23

Which two pathways utilize carbamoyl phosphate?

Answer 23

De novo pyrimidine synthesis and urea cycle

Question 24

Cofactor? dUMP ---\> dTMP

Answer 24

N⁵N¹⁰- methylene THF (DHF is product of this reaction, needs to be reduced back to THF)

Question 25

Which substrate of pyrimidine synthesis is also involved in urea cycle?

Answer 25

Carbamoyl phosphate

Question 27

Which drug inhibits thymidylate synthase?

Answer 27

5-FU (Inhibits dUMP ---\> dTMP)

Question 28

Steps in purine synthesis

Answer 28

Ribose-5-P ---\> PRPP ---\> IMP ----\> **AMP + GMP**

Question 29

MOA mycophenolate and ribavirin

Answer 29

Inhibit IMP dehydrogenase (Inhibit IMP ---\> GMP)

Question 30

Enzyme? Carbamoyl phosphate ---\> Orotic acid

Answer 30

Dihydroorotic acid dehydrogenase

Question 31

Which drug would result in increased levels of dUMP?

Answer 31

5-FU (Inhibits thymidylate synthase, so inhibits dUMP ---\> dTMP)

Question 32

Would THF levels be increased or reduced due to treatment with MTX, TMP, or pyrimethamine?

Answer 32

Reduced (Inhibits dihydrofolate reductase = DHF ---\> THF)

Question 33

Enzyme? Glutamine + CO2 ---\> Carbamoyl phosphate

Answer 33

Carbamoyl phosphate synthetase II

Question 34

Which drug inhibits dihydroorate dehydrogenase?

Answer 34

Leflunomide

Question 35

Which two cofactors are needed for both de novo purine and de novo pyrimidine synthesis?

Answer 35

THF, aspartate

Question 36

Cofactor? Carbamoyl phosphate ---\> Orotic acid

Answer 36

Aspartate