RT Journal Article SR Electronic T1 Functional and structural resilience of the active site loop in the evolution of Plasmodium lactate dehydrogenase JF bioRxiv FD Cold Spring Harbor Laboratory SP 386029 DO 10.1101/386029 A1 Jacob D. Wirth A1 Jeffrey I. Boucher A1 Joseph R. Jacobowitz A1 Scott Classen A1 Douglas L. Theobald YR 2018 UL http://biorxiv.org/content/early/2018/08/07/386029.abstract AB 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. Apicomplexan loop conservation suggests that a particular insertion sequence was required to evolve LDH specificity, and we previously showed (Boucher 2014) that a tryptophan in the insertion, W107f, is essential for activity and specificity. However, the roles of other residues in the loop are currently unknown. Here we show that PfLDH activity is remarkably 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 therefore has high potential to develop resistance to drugs that target its distinctive active site.