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.
D001379:Azathioprine / Q000097:blood*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007291:Inosine Monophosphate / Q000031:analogs & derivatives / Q000097:blood*; D007292:Inosine Nucleotides / Q000097:blood*; D015122:Mercaptopurine / Q000097:blood*; D010084:Oxidation-Reduction; D010710:Phosphates / Q000494:pharmacology; D010754:Phosphoribosyl Pyrophosphate / Q000097:blood; D011758:Pyrroles / Q000494:pharmacology*; D013866:Thioguanine / Q000378:metabolism*; D013873:Thionucleotides / Q000097:blood*
D007292:Inosine Nucleotides; D010710:Phosphates; D011758:Pyrroles; D013873:Thionucleotides; D007291:Inosine Monophosphate; C015485:delta-1-pyrroline-5-carboxylate; D010754:Phosphoribosyl Pyrophosphate; C003449:thioinosinic acid; D015122:Mercaptopurine; D013866:Thioguanine; D001379:Azathioprine