Wirth Jacob D, Boucher Jeffrey I, Jacobowitz Joseph R, Classen Scott, Theobald Douglas L
Department of Biochemistry , Brandeis University , Waltham , Massachusetts 02454 , United States.
Biochemistry. 2018 Nov 13;57(45):6434-6442. doi: 10.1021/acs.biochem.8b00913. Epub 2018 Nov 2.
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 because of its unique active site. The conservation of the apicomplexan loop suggests that a precise insertion sequence was required for the evolution of 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 great potential to develop resistance to drugs designed to target its distinctive active site loop.
疟原虫病原体恶性疟原虫（Pf）是顶复门的一员，它通过在关键活性位点环中插入五个残基，从祖先苹果酸脱氢酶（MDH）独立进化出一种高度特异性的乳酸脱氢酶（LDH）。由于其独特的活性位点，PfLDH被广泛认为是一个有吸引力的药物靶点。顶复门环的保守性表明，LDH特异性的进化需要精确的插入序列。除了单个关键色氨酸W107f外，环中残基的功能和结构作用目前尚不清楚。在这里，我们表明该环对突变具有显著的抗性，因为活性对环的同一性和长度的剧烈扰动具有弹性。因此，只要在适当位置包含一个色氨酸，替代插入就可能进化出LDH特异性。PfLDH很可能有很大潜力对针对其独特活性位点环设计的药物产生抗性。
