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The Source of Purines and Pyrimidines in Plasmodium Berghei^*

The effectiveness of many antimalarial drugs depends, at least in part, upon their ability to prevent the replication of deoxyribonucleic acid (DNA) and the synthesis of ribonucleic acid (RNA) in the nucleus of the malaria parasite, thereby killing it. This replication requires purine and pyrimidine nucleotides; we sought their sources in Plasmodium berghei with the view that this knowledge might lead to an agent that would block the supply, or their incorporation into nucleic acids, or both. Erythrocytes parasitized with P. berghei were exposed to a radiolabeled purine or purine nucleoside. The cells were washed, the leukocytes removed by centrifugation (in pyrimidine nucleoside experiments), and the erythrocytes precipitated with 10% trichloracetic acid (TCA). The radioactivity of the supernatant fluid was measured to determine the uptake of radioactivity by the erythrocytes. The precipitate was washed and heated at 90°C in 10% TCA for 30 minutes to release the radioactive substances incorporated into the DNA and RNA of the parasites. We found that there was a rapid and specific incorporation of adenosine, deoxyadenosine, adenine, and guanosine (all nucleotide precursors) into the nucleic acid of the parasites. Pyrimidine nucleosides do not penetrate the parasite membrane and must be synthesized de novo by it. We found a pyrimidine biosynthetic enzyme (aspartate transcarbamylase) associated with the parasite. We concluded that agents that will block the purine-uptake and incorporation mechanisms, and pyrimidine antimetabolites, may be important in the chemotherapy of malaria.

Accepted for publication August 20, 1969.

^* This work was carried out under terms of Contract No. DA-49-193-MD-2767 between the U.S. Army Medical Research and Development Command and the Board of Governors of West Virginia University and is contribution No. 518 from the Army Research Program on Malaria. Support of Dr. Tremblay by NIH grant HD 03168 is appreciated.

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