Purine and pyrimidine synthesis Flashcards
Which substrate in pyrimidine synthesis would be lowered due to 5-FU treatment?
dTMP
(Inhibitis thymidylate synthase = dUMP —> dTMP)
What is required for de novo purine synthesis?
Aspartate, glutamine, glycine, THF
Cofactor?
Orotic acid —> UMP
PRPP
MOA of hydroxyurea?
Ribonucleotide reductase
(Inhibits UDP –> dUDP)
Which substrate in purine synthesis would be lowered as a result of treatment with ribavirin or mycophenolate?
GMP
(Inhibit IMP dehydrogenase, so inhibit IMP —> GMP)
Which substrate in pyrimidine synthesis would be higher with TMP, pyrimethamine, or MTX treatment? Lower?
dUMP higher
dTMP lower
(Inhibits DHFR = needed for reduction of DHF to THF to regenerate N5N10-methylene THF, the cofactor for dUMP —> dTMP reaction)
Enzyme?
UDP —> dUDP
Ribonucleotide reductase
Enzyme?
dUMP –> dTMP
Thymidylate synthase
Which enzyme activates 6-MP?
HGPRT
Which substrate in purine synthesis would be lower as a result of treatment with 6-mercaptopurine?
IMP
(Inhibits PRPP —> IMP)
Which drug inhibits pyrimidine synthesis is bacteria specifically? Protozoa specifically?
Trimethoprim
Pyrimethamine
(DHFR inhibitors)
MOA leflunomide?
Inhibits dihydroorate dehydrognase
(Inhibits carbamoyl phosphate —> orotic acid)
Which drug would cause higher levels of PRPP?
6-mercaptopurine
(Inhibits PRPP —> IMP)
Elevated DHF levels are indicative of treatment with which drugs?
Trimethoprim
Methotrexate
Pryrimethamine
Steps in pyrimidine synthesis
Glutamine + CO2 —> Carbamoyl phosphate —> Orotic acid —> UMP —> UDP —> CTP + dUDP —> dUMP —> dTMP
Which step in purine synthesis is inhibited by 6-mercaptopurine?
PRPP —> IMP
Which step in pyrimidine synthesis is impaired in orotic aciduria?
Orotic acid —> UMP
Which enzyme is needed for degradation of 6-MP?
TPMT and xanthine oxidase
(activated by HGPRT)
Enzyme?
Ribose-5-P —> PRPP
PRPP synthetase
Which drug would results in high levels of UDP?
Hydroxyurea
(Inhibits ribonucleotide reductase, so inhibits UDP —> dUDP)
Enzyme?
DHF —> THF
Dihydrofolate reductase
Which substrate in pyrimidine synthesis would be lowered as a result of hydroxyurea treatment?
dUDP
(Inhibits ribonucleotide reductase, so inhibits UDP —> dUDP)
Which drugs would cause higher levels of IMP?
Ribavirin, mycophenolate
(Inhibit IMP dehydrogenase, so inhibits IMP —> GMP)
Which two pathways utilize carbamoyl phosphate?
De novo pyrimidine synthesis and urea cycle
Cofactor?
dUMP —> dTMP
N5N10- methylene THF
(DHF is product of this reaction, needs to be reduced back to THF)
Which substrate of pyrimidine synthesis is also involved in urea cycle?
Carbamoyl phosphate
Which drug inhibits thymidylate synthase?
5-FU
(Inhibits dUMP —> dTMP)
Steps in purine synthesis
Ribose-5-P —> PRPP —> IMP —-> AMP + GMP
MOA mycophenolate and ribavirin
Inhibit IMP dehydrogenase
(Inhibit IMP —> GMP)
Enzyme?
Carbamoyl phosphate —> Orotic acid
Dihydroorotic acid dehydrogenase
Which drug would result in increased levels of dUMP?
5-FU
(Inhibits thymidylate synthase, so inhibits dUMP —> dTMP)
Would THF levels be increased or reduced due to treatment with MTX, TMP, or pyrimethamine?
Reduced
(Inhibits dihydrofolate reductase = DHF —> THF)
Enzyme?
Glutamine + CO2 —> Carbamoyl phosphate
Carbamoyl phosphate synthetase II
Which drug inhibits dihydroorate dehydrogenase?
Leflunomide
Which two cofactors are needed for both de novo purine and de novo pyrimidine synthesis?
THF, aspartate
Cofactor?
Carbamoyl phosphate —> Orotic acid
Aspartate
