Functional and structural resilience of the active site loop in the evolution of Plasmodium lactate dehydrogenase.

The malarial pathogen Plasmodium falciparum (Pf) is a member of the Apicomplexa， which independently evolved a highly specific lactate dehydrogenase (LDH) from an ancestral malate dehydrogenase (MDH) via a five-residue insertion in a key active site loop. PfLDH is widely considered an attractive drug target due to its unique active site. The conservation of the apicomplexan loop suggests that a precise insertion sequence was required to evolve LDH specificity. Aside from a single critical tryptophan， W107f， the functional and structural roles of residues in the loop are currently unknown. Here we show that the loop is remarkably robust to mutation， as activity is resilient to radical perturbations of both loop identity and length. Thus， alternative insertions could have evolved LDH specificity as long as they contained a tryptophan in the proper location. PfLDH likely has high potential to develop resistance to drugs designed to target its distinctive active site loop.