Therapeutic Applications of Purine and Pyrimidine Metabolism By Brian Kim and Jessica Swavely
Mechanisms of Action
1) Synthetic Nucleotide Analog
2) Cofactor Analog or Competitor
3) Folate Analog
What Pathway Do I Affect?
1) Folate Cycle (Affects both purine and pyrimidine synthesis)
2) Pyrimidine Synthesis
3) Purine Synthesis
Methotrexate and Aminopterin
Methotrexate is also used in severe psoraisis, Crohn's disease, and rheumatoid arthritis
Sulfamethoxazole/Trimethoprim (Bactrim or Septra)
Allopurinol (Zyloprim)
5-Fluorouracil
Primarily an inhibitor of thymidylate synthase
Creates FdUMP, FdUTP and FUTP
Capecitabine (Xeloda)
Transformed to 5-fluorouracil in vivo
Works to inhibit thymidylate synthase
Treatment for: colon cancer, metastatic breast and colorectal cancer
Vistoguard (Uridine Triacetate)
5-fluorouracil overdose (prodrug)
Deacetylated via nonspecific esterases
Competitively inhibits 5-FU induced cell death
Treatment for hereditary orotic acidemia and 5-Fluorouracil overdose
Azaserine
Glutamine analog
Blocks VI synthase (5th step in inosine monophosphate synthesis)
6-mercaptopurine
Competes with purine derivatives (hypoxanthine and guanine) for hypoxanthine-guanine phosphoribosyltransferase
Converted to thio inosine monophosphate (TIMP) – inhibits IMP-dependent reactions
Diazanorleucine
Competitively inhibits glutamate-dependent enzymes