Orotidylate-metabolizing enzymes of the human malarial parasite, Plasmodium falciparum, differ from host cell enzymes.

Orotate phosphoribosyltransferase and orotidylate decarboxylase from mammalian sources reside on a bifunctional protein. In such a system, orotidylate, the product of orotate phosphoribosyltransferase is preferentially channeled to orotidylate decarboxylase and does not equilibrate with the assay medium. In contrast, we found that orotidylate was released into the medium during the conversion of orotate to uridylate by cell-free extract of Plasmodium falciparum. Furthermore, orotate phosphoribosyltransferase and orotidylate decarboxylase from this parasite were resolved from each other by biospecific elution from blue Sepharose, indicating that the parasite enzymes do not exist as a bifunctional protein. Finally, orotate phosphoribosyltransferase from P. falciparum was found to be much more sensitive to inhibition by mercurial reagents than the red blood cell enzyme. These biochemical differences between host and parasite enzymes offer a possible basis for the design of novel antimalarial agents.