2015 Antineoplastics

Review of purine synthesis

Five critical components:

1. The souce of ribose is 5-phosphoribosyl-1-pyrophosphate (PRPP). Synthesis of PRPP is catalyzed by purine nucleoside phosphorylase (PNP).

2. The first committed step in purine synthesis is the formation of 5-phosphoribosylamine via the enzyme PRPP glutamylamidotransferase.

3. 6-MP and 6-TG enter via the "salvage pathway" where PRPP reacts with hypoxanthine or guanine bases to form IMP or GMP, respectively. This reaction is catalyzed by hypoxanthine-guanine phosphoribosyl transferase (HGPRT).

4. GMP is converted to GDP by guanylyl kinase. This is the step that is blocked by 6-MP and 6-TG, causing a buildup of GMP.

5. There are numerous negative feedback pathways mediated by increased concentrations of GMP. The most critical is the inhibition of the first two steps in the purine biosynthetic pathway (ribose-5-phosphate → PRPP → 5-phosphoribosylamine). 6-MP and 6-TG therefore shut down purine sythesis by limiting both the neosysnthesis and salvage pathways.

• Drug cards
• Nucleotide biochemistry
• Types
• Nucleotide synthesis inhibitors
  • Folic acid analogues
    • Mechanism of action
    • Resistance
    • Pharmacokinetics
    • Therapeutic Uses
    • Toxicity
    • Leucovorin rescue
  • Pyrimidine analogues
    • Mechanism of action
    • Resistance
    • Pharmacokinetics
    • Therapeutic Uses
    • Toxicity
  • Purine analogues
    • Review of purine synthesis
    • Mechanism of action
    • Resistance
    • Pharmacokinetics
    • Therapeutic Uses
    • Toxicity
    • Tumour lysis syndrome
• DNA synthesizing enzyme inhibitors