Pyrroline-5-carboxylate stimulates the conversion of purine antimetabolites to their nucleotide forms by a redox-dependent mechanism.

The activation of purine antimetabolites to their respective nucleotides is a step critical to their effectiveness as chemotherapeutic agents. Erythrocytes, with their relatively simple purine metabolism, are useful as a model for identifying mechanisms which enhance this 5-phosphoribosyl 1-pyrophosphate (P-Rib-PP)-dependent activation. We previously showed that pyrroline-5-carboxylate, a physiologic intermediate in the interconversions of proline, ornithine, and glutamate, markedly stimulated the pentose phosphate pathway, increased the formation of P-Rib-PP, and increased purine incorporation into nucleotides. We now report that the events initiated by pyrroline-5-carboxylate markedly increased the activation of 6-thiohypoxanthine, 6-thioguanine, and azathioprine to their respective nucleotides in intact human erythrocytes. The mechanism of this effect was directly demonstrated in studies using the conversion of hypoxanthine to inosine monophosphate as a model for pyrroline-5-carboxylate-mediated stimulation of P-Rib-PP-dependent nucleotide formation. Since the P-Rib-PP-dependent activation of these chemotherapeutic agents may be important to their clinical effectiveness, the events initiated by pyrroline-5-carboxylate may provide new insight into the nature of tumor sensitivity and resistance to these agents.
AuthorsG C Yeh, J M Phang
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 258 Issue 16 Pg. 9774-9 (Aug 25 1983) ISSN: 0021-9258 [Print] UNITED STATES
PMID6193109 (Publication Type: Journal Article)
Chemical References
  • Inosine Nucleotides
  • Phosphates
  • Pyrroles
  • Thionucleotides
  • Inosine Monophosphate
  • delta-1-pyrroline-5-carboxylate
  • Phosphoribosyl Pyrophosphate
  • thioinosinic acid
  • 6-Mercaptopurine
  • Thioguanine
  • Azathioprine
  • 6-Mercaptopurine (blood)
  • Azathioprine (blood)
  • Erythrocytes (drug effects, metabolism)
  • Humans
  • Inosine Monophosphate (analogs & derivatives, blood)
  • Inosine Nucleotides (blood)
  • Oxidation-Reduction
  • Phosphates (pharmacology)
  • Phosphoribosyl Pyrophosphate (blood)
  • Pyrroles (pharmacology)
  • Thioguanine (metabolism)
  • Thionucleotides (blood)

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