Drugs Affecting Nucleotide Metabolism

Question 1

allopurinol

Answer 1

used to treat gout

oxidized by hepatic xanthine oxidase to alloxanthine, which binds irreversibly to xanthine oxidase

this inhibits it and thus it cannot oxidize xanthine further to uric acid

the accumulated xanthine and hypoxanthine is salvaged by HGRPT to IMP and XMP, inhibiting new purine synthesis

Question 2

methotrexate

Answer 2

used in cancer chemotherapy

binds to dihydrofolate reductase, causing a shortage of THF that is needed for purine and pyrimidine synthesis in rapidly dividing cells- particularly useful in cancer

however, cells can be rescued by hypoxanthine and thymidine.

used in high dose for a short time followed by rescue with reduced folic acid

can also treat chroni inflammatory illnesses

Question 3

sulfanilamdie

Answer 3

antibacterial agent

analog of p-aminobenzoic acid, and intermediate of folic acid synthesis in bacteria. selective inhibitor of de novo folic acid synthesis in bacteria

Question 4

tripethoprim

Answer 4

antibacterial

folate analog that binds to dihydrofolate reductase of bacteria much more strongly than mammals

Question 5

fluorouracil

Answer 5

used in cancer therapy

pyrimidine analog that is inert until eventually onverted to F-dUMP, which binds thymidylate synthase, inactivating it and depleting thymidine pools

Question 6

mercapoturine

Answer 6

anti-tumor drug

tumor cell forms 6-mercaptopurine ribonucleotide using HGPRT and PRPP, which accumulates in the cell and inhibits PRPP aminotransferase and thus purine synthesis

Question 7

cytosine arabinoside

Answer 7

cancer therapy

Ara-C is converted to Ara-CMP by deoxycytidine kinase, then to Ara-CTP. this is the incorporated into a DNA strand, halting DNA synthesis

Question 8

acycloguanosine

Answer 8

anti-viral (herpes)

acycloguanosine is activated to the monophosphate form by viral thymidine kinase which does not exist in the host. acycloguanosine monophosphate is then phosphorylated by host enzymes to the triphosphate form. this then is incorporated during viral replication and is terminates the viral DNA chain

Question 9

azldothymide

Answer 9

anti-viral (HIV)

phosphorylated to the triphosphate form via cellular kinases and inhibits the HIB-DNA polymerase, which is 100 fold more sensitive than the host polymerase