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Chromatographic Studies of Purine Metabolism

VI. Inhibition of Inosine Phosphorylase by 6-Mercaptopurine¹

Kettering-Meyer Laboratory Southern Research Institute,² Birmingham, Alabama

The short-term effects of 6-mercaptopurine upon the intracellular metabolic pools of purines have been studied in Escherichia coli that were assimilating formate-¹⁴C, inosine-¹⁴C, adenosine-¹⁴C, guanosine-¹⁴C, or hypoxanthine-¹⁴C. Following the 15-min assimilation of the radioactive substrate, the soluble cell fraction components were separated by paper chromatography and assayed for radioactivity.

The strongest metabolic effect of 6-mercaptopurine observed was a large accumulation of inosine accompanied by a large decrease of hypoxanthine. This was taken as evidence for a previously unreported blockade of inosine phosphorylase. Although this effect was observed at 6-mercaptopurine levels as low as 5 µg/ml, at which level there was no inhibition of growth, it appeared to account for little if any of the growth inhibition at higher 6-mercaptopurine levels.

The known effect of 6-mercaptopurine in blocking the conversion of inosinic acid to adenylic acid was indeed in evidence, but the block was not sufficiently strong to act as a rate-limiting factor for growth.

¹ Supported by Cancer Chemotherapy National Service Center, National Cancer Institute, under NIH Contract No. SA-43-ph-2433, and by grants from the Alfred P. Sloan Foundation and the Charles F. Kettering Foundation.

² Affiliated with the Sloan-Kettering Institute for Cancer Research, New York, N. Y.

Received 3/ 8/65. Revised 7/ 9/65.