The Plasmodium falciparum bifunctional ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, enables a well balanced polyamine synthesis without domain-domain interaction

In the human malaria parasite Plasmodium falciparum (Pf), polyamines are sy nthesized by a bifunctional enzyme that possesses both ornithine decarboxyl ase (ODC) and S-adenosyl-L-methionine decarboxylase (AdoMetDC) activities. The mature enzyme consists of the heterotetrameric N-terminal AdoMetDC and the C-terminal dimeric ODC, which results in the formation of a heterotetra meric complex. For the native bifunctional protein a half-life longer than 2 h was determined, which is in contrast to the extreme short half-life of its mammalian monofunctional counterparts. The biological advantage of the plasmodial bifunctional ODC/ AdoMetDC might be that the control of polyamin e synthesis is achieved by only having to regulate the abundance and activi ty of one protein. An interesting feature in the regulation of the bifuncti onal protein is that putrescine inhibits PfODC activity similar to 10-fold more efficiently than the mammalian ODC activity, and in contrast to the ma mmalian AdoMetDC the activity of the PfAdoMetDC domain is not stimulated by the diamine. To analyze post-translational processing, polymerization, and domain-domain interactions, several mutant proteins were generated that ha ve single mutations in either the PfODC or PfAdoMetDC domains. The exchange of amino acids essential for the activity of one domain had no effect on t he enzyme activity of the other domain. Even prevention of the post-transla tional cleavage of the AdoMetDC domain or ODC dimerization and thus the int erference with the folding of the protein hardly affected the activity of t he partner domain. In addition, inhibition of the activity of the PfODC dom ain had no effect on the activity of the PfAdoMetDC domain and vice versa. These results demonstrate that no domain-domain interactions occur between the two enzymes of the bifunctional PfODC/AdoMetDC and that both enzymatic activities are operating as independent catalytic sites that do not affect each other.