Drugs Affecting Nucleotide Metabolism

Question 1

Allopurinol

Answer 1

• Oxidized by xanthine oxidase to alloxanthine, which binds to enzyme and inhibits it irreversibly; hypoxanthine and xanthine oxidized to uric acid
• results in increase in purine nucleotide pool –> inhibits PRPP synthetase and PRPP-amido transferase in purine biosynthesis

Question 2

Antifolate class

Answer 2

ex. methotrexate, aminopteri, trimethoprim, sulfanilamide

inferfere w/ formation of THF (prevent purine and pyrimidine biosynthesis)

Question 3

Methotrexate

Answer 3

binds dihydrofolate reductase (DHFR) –> cells accumulate DHF, are depleted of THF –> decreased purine and pyrimidine biosynth

Question 4

Sulfanilamide

Answer 4

analog of PABA (intermediate of folic acid synthesis in many bacteria)
- many bacteria req de novo folic acid synth, so this selectively inhibits bacterial growth

Question 5

trimethoprim

Answer 5

folate analog that binds to DHFR of microorganisms more tightly than to mammalian DHFR –> inhibits parasite and bacterial infections (in combo w/ sulfas)

Question 6

Fluorouracil

Answer 6

• incorporated into F-UDP -> F-dUDP -> F-dUMP

- F-dUMP forms a complex w/ thymidylate synthase, preventing pyrimidine synthesis and DNA synthesis

Question 7

Mercaptopurine

Answer 7

Anti-tumor drug: converted into nucleotide form of 6-MP, acts as a negative effector of PRPP-amidotransferase (1st committed step of purine biosynth)

Question 8

Cytosine Arabinose (Ara-C)

Answer 8

AntiConverted into Ara-CMP –> di and tri phosphorylated forms producing Ara-CTP
- Ara-CTP is a chain terminating AA = stops further DNA synthesis

Question 9

Acycloguanosine/acyclovir

Answer 9

• treatment for herpes virus
• activated to monophosphate from by HSV-thymidine kinase. in infected cells –> di- and tri-phosphorylated forms
• Acycloguanosine triphosphate is chain terminating for viral DNA chain

Question 10

Azidothymidine (AZT)

Answer 10

• treatment for HIV
• phosphorylated to AZT-triphosphate
• AZT triphosphate inhibits HIV-DNA polymerase

resistance can be developed easily, this is whyt a cocktail of inhibitors against different targets is given