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首页> 外文期刊>The FEBS journal >The structure of Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase reveals the basis of sulfa resistance
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The structure of Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase reveals the basis of sulfa resistance

机译：羟甲吡喃氨基甲基二氨基吡啶蛋白磷磷酶 - 二氢丙烯酸二氢丙酯合酶的结构揭示了磺基抗性的基础

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摘要

The clinical efficacy of sulfa drugs as antimalarials has declined owing to the evolution of resistance in Plasmodium falciparum (Pf) malaria parasites. In order to understand the basis of this resistance and to design more effective antimalarials, we have solved 13 structures of the bifunctional enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK)-dihydropteroate synthase (DHPS) from wild-type (WT) P. falciparum and sulfa-resistant mutants, both as apoenzyme and as complexes with pteroate (PTA) and sulfa derivatives. The structures of these complexes show that PTA, which effectively inhibits both the WT and mutants, stays in active sites without steric constraint. In contrast, parts of the sulfa compounds situated outside of the substrate envelope are in the vicinity of the resistance mutations. Steric conflict between compound and mutant residue along with increased flexibility of loop D2 in the mutants can account for the reduced compound binding affinity to the mutants. Kinetic data show that the mutants have enhanced enzyme activity compared with the WT. These PfDHPS structural insights are critical for the design of novel, substrate envelope-compliant DHPS inhibitors that are less vulnerable to resistance mutations. Databases The data reported in this paper have been deposited in the Protein Data Bank, . PDB ID codes: for apoWT; , , and for PTA complexes of WT, A437G (3D7), and V1/S; , , and for STZ-DHP complexes of WT, 3D7, and V1/S; , , and for SDX-DHP complexes of WT, 3D7, and W2; , , and for Pterin/pHBA complexes of WT, TN1, and W2.
机译：由于疟原虫（PF）疟疾寄生虫抗性的抗性的演变，磺胺药作为抗疟药的临床疗效有所下降。为了了解这种阻力的基础和设计更有效的抗疟药，我们已经从野生型（WT）中溶解了双官能酶6-羟甲基-7,8-二氢化术蛋白溶解酶（HPPK）-diHydropteroate合酶（DHPS）的结构）P. falciparum和磺抗体突变体，既是孕酶，也可作为丙酸盐（PTA）和磺胺衍生物的复合物。这些配合物的结构表明，PTA有效地抑制WT和突变体，在没有空间约束的情况下停留在有源点。相反，位于基板包络外部的磺化化合物的部分位于电阻突变附近。化合物和突变残留物之间的空间冲突以及突变体中环D2的柔韧性增加可以考虑对突变体的降低的复合物结合亲和力。动力学数据表明，与wt相比，突变体具有增强的酶活性。这些PFDHPS结构洞察对于设计的设计至关重要，符合符合抗性突变的易受损伤的纯基板包膜副的DHPS抑制剂。数据库本文报告的数据已存放在蛋白质数据库中。 PDB ID代码：对于Apowt; ，以及WT，A437G（3D7）和V1 / s的PTA复合物; ，以及WT，3D7和V1 / s的STZ-DHP复合物; ，以及WT，3D7和W2的SDX-DHP复合物; ，以及WT，TN1和W2的pterin / phba复合物。

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