Pyrroline-5-carboxylate stimulates the conversion of purine antimetabolites to their nucleotide forms by a redox-dependent mechanism.
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| Abstract |
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.
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| Authors | G C Yeh, J M Phang |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 258 Issue 16 Pg. 9774-9 (Aug 25 1983) ISSN: 0021-9258 [Print] United States |
| PMID | 6193109 (Publication Type: Journal Article) |
| Chemical References |
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