Every year, there are over 100 million new malarial infections, resulting in over a million deaths. As revealed by recent genome sequencing efforts, Plasmodium parasites responsible for this deadly disease comprise proteins with unique inserts. In many instances, these inserts are low complexity regions (LCR) that are found not just between globular domains. Functional implications of these inserts may reveal the remarkable adaptive abilities and inspire novel strategy for anti-malarial drug discovery, but are thus far unknown.

Where there exist a few solved Plasmodium protein structures with predicted LCR inserts, these regions are typically disordered or turn out to be connecting loops. We have solved the structures of orotidine 5?-monophosphate decarboxylase (OMPDC) from four Plasmodium species -- P. falciparum, P. vivax, P. yoelii, and P. berghei. The enzyme OMPDC is involved biosynthesis of pyrimidines and is structurally well studied from other organisms. In all cases, low complexity inserts can be readily identified by sequence analysis but are different amongst the Plasmodium species. Specifically, in this region, OMPDC from P. falciparum, P. yoelii, and P. berghei feature a notably higher number of asparagines while P. vivax and P. knowlesi tend to be serine-rich.

The predicted LCR inserts are well defined in our Plasmodium OMPDC structures. In all cases, these inserts are realized as an extra helical fold outside the typical OMPDC TIM-barrel from other organisms. This fold is seen in all Plasmodium OMPDC despite sequence differences in this region. It does contain the residues involved in substrate or product binding, and is not involved in the dimeric interface of the enzyme.

There are previous reports of Plasmodium OMPDC forming a tetrameric complex with orotate phosphoribosyltransferase (OPRT), another enzyme involved in pyrimidine biosynthesis. Therefore, we propose that this insert is the OMPDC-OPRT interacting region. For the first time, we have not only solved structures with Plasmodium-specific inserts well defined but are able to use the structures to infer their specific function.