Biochem Lecture 38 (Drugs Affecting Nucleotide Metabolism)

Question 1

Allopurinol

Tx for?

Class?

Mechanism?

Answer 1

tx for:

gout

class

purine analog

mechanism

1) looks like hypoxanthine and is oxidized by xanthine oxidase but makes alloxanthine which binds irreversibly to xanthine oxidase
2) resulting hypoxanthine back-up is salvaged by HGPRT to IMP and XMP; this incr purine nuleotide pool is neg. feedback to PRPP-synthetase and PRPP-amdiotransferase (the rate-limiting enzymes in purine synth)

Question 2

Methotrexate

Tx for?

Class?

Mechanism?

Answer 2

Tx for

cancer chemo; others including: RA, Crohn’s

Class

Antifolates

Mechanism

prevents formation of THF, DHF accumulates; lack of THF prevents purine and pyrimidine biosynth; affects rapidly growing cells;

rescue w/ reduced folic acid after tx

Question 3

Sulfanilamide

Tx for?

Class?

Mechanism?

Answer 3

Tx for

bacterial infection

Class

antifolates

Mechanism

bacteriostatic antibiotic; PABA analog (= intermeditate in folic acid snyth in bacteria); usually given with trimethoprim

Question 4

Trimethoprim

Tx for?

Class?

Mechanism?

Answer 4

Tx for

bacterial infection and protozoa infestation (e.g. malaria)

Class

antifolates

Mechanism

inhibits DHFR (dihydrofolate reductase); usually given with sulfanilamide

Question 5

Fluorouracil

Tx for?

Class?

Mechanism?

Answer 5

Tx for

cancer

Class

pyrimidine analog

Mechanism

1st salvaged: 5-fluorouracil—>F-UMP—>F-UDP—>F-dUDP—>F-dUMP

F-dUMP suicide inhibits thymidylate synthase—>cell thymidine pools decr—>halts DNA synth and therefore cell division

Question 6

Mercaptopruine

Tx for?

Class?

Mechanism?

Answer 6

Tx for

cancer (“Anti-tumor”)

Class

purine analog (“thiopurine”)

Mechanism

6-MP + PRPP—HGPRT—>nucleotide form; accumulates in cell and inhibits PRPP-amidotransferase, the “committed step” in purine synth

Question 7

Ara-C

Tx for?

Class?

Mechanism?

Answer 7

Ara-C = cytosine arabinoside

Tx for

anti-cancer

Class

pyrimidine analog

Mechanism

Ara-C—>—>—>Ara-CTP—>incorp’d into growing DNA strand and stops DNA synth

Question 8

Acyclovir

Tx for?

Class?

Mechanism?

Answer 8

Acyclovir = acycloguanosine

Tx for

Herpes

Class

purine analog

Mechanism

phosphorylated by viral—thymidine kinase—>tri-P form; incorporated into growing DNA by viral DNA pol causing chain termination

Question 9

AZT

Tx for?

Class?

Mechanism?

Answer 9

**AZT = azidothymidine **

Tx for

HIV

Class

nucleoside analog RT inhibitor

Mechanism

phosphorylated to AZT-TP which blocks viral reverse transcriptase (an RNA-dep DNA pol); RT has 100x higher affinity for AZT-TP than host DNA pol