The unusual kinetics of lactate dehydrogenase of Schistosoma mansoni and their role in the rapid metabolic switch after penetration of the mammalian host

IF 3.7 2区医学 Q1 PARASITOLOGY

International journal for parasitology Pub Date : 2024-06-01 DOI:10.1016/j.ijpara.2024.03.005

Michiel L. Bexkens , Olivier M.F. Martin , Jos M. van den Heuvel , Marion G.J. Schmitz , Bas Teusink , Barbara M. Bakker , Jaap J. van Hellemond , Jurgen R. Haanstra , Malcolm D. Walkinshaw , Aloysius G.M. Tielens

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Abstract

Lactate dehydrogenase (LDH) from Schistosoma mansoni has peculiar properties for a eukaryotic LDH. Schistosomal LDH (SmLDH) isolated from schistosomes, and the recombinantly expressed protein, are strongly inhibited by ATP, which is neutralized by fructose-1,6-bisphosphate (FBP). In the conserved FBP/anion binding site we identified two residues in SmLDH (Val187 and Tyr190) that differ from the conserved residues in LDHs of other eukaryotes, but are identical to conserved residues in FBP-sensitive prokaryotic LDHs. Three-dimensional (3D) models were generated to compare the structure of SmLDH with other LDHs. These models indicated that residues Val187, and especially Tyr190, play a crucial role in the interaction of FBP with the anion pocket of SmLDH. These 3D models of SmLDH are also consistent with a competitive model of SmLDH inhibition in which ATP (inhibitor) and FBP (activator) compete for binding in a well-defined anion pocket. The model of bound ATP predicts a distortion of the nearby key catalytic residue His195, resulting in enzyme inhibition. To investigate a possible physiological role of this allosteric regulation of LDH in schistosomes we made a kinetic model in which the allosteric regulation of the glycolytic enzymes can be varied. The model showed that inhibition of LDH by ATP prevents fermentation to lactate in the free-living stages in water and ensures complete oxidation via the Krebs cycle of the endogenous glycogen reserves. This mechanism of allosteric inhibition by ATP prevents the untimely depletion of these glycogen reserves, the only fuel of the free-living cercariae. Neutralization by FBP of this ATP inhibition of LDH prevents accumulation of glycolytic intermediates when S. mansoni schistosomula are confronted with the sudden large increase in glucose availability upon penetration of the final host. It appears that the LDH of S. mansoni is special and well suited to deal with the variations in glucose availability the parasite encounters during its life cycle.

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曼氏血吸虫乳酸脱氢酶的不寻常动力学及其在侵入哺乳动物宿主后的快速代谢转换中的作用。

曼氏血吸虫的乳酸脱氢酶（LDH）具有真核生物 LDH 的特殊性质。从血吸虫中分离出的血吸虫 LDH（SmLDH）和重组表达的蛋白都受到 ATP 的强烈抑制，而 ATP 又被 1,6-二磷酸果糖（FBP）中和。在保守的 FBP/阴离子结合位点，我们发现 SmLDH 中的两个残基（Val187 和 Tyr190）与其他真核生物 LDH 中的保守残基不同，但与对 FBP 敏感的原核生物 LDH 中的保守残基相同。为了比较 SmLDH 与其他 LDH 的结构，我们生成了三维（3D）模型。这些模型表明，残基 Val187，尤其是 Tyr190 在 FBP 与 SmLDH 阴离子口袋的相互作用中起着关键作用。这些 SmLDH 的三维模型也与 SmLDH 的竞争性抑制模型相一致，其中 ATP（抑制剂）和 FBP（激活剂）在一个定义明确的阴离子口袋中竞争结合。根据结合 ATP 的模型预测，附近的关键催化残基 His195 会发生变形，从而导致酶抑制作用。为了研究血吸虫中 LDH 的这种异构调节可能发挥的生理作用，我们制作了一个动力学模型，其中糖酵解酶的异构调节可以改变。该模型显示，ATP 对 LDH 的抑制可防止其在水中自由生活阶段发酵成乳酸，并确保内源性糖原储备通过克雷布斯循环完全氧化。ATP 的这种异构抑制机制可防止这些糖原储备的过早耗尽，而糖原储备是自由生活的蛛网膜虫的唯一燃料。当曼氏血吸虫穿透最终宿主时，葡萄糖供应量突然大幅增加，FBP 对 LDH 的这种 ATP 抑制作用的中和作用可防止糖酵解中间产物的积累。由此看来，曼氏血吸虫的 LDH 比较特殊，非常适合处理寄生虫在其生命周期中遇到的葡萄糖供应变化。

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来源期刊

International journal for parasitology 医学-寄生虫学

CiteScore

8.40

自引率

2.50%

发文量

审稿时长

23 days

期刊介绍： International Journal for Parasitology offers authors the option to sponsor nonsubscriber access to their articles on Elsevier electronic publishing platforms. For more information please view our Sponsored Articles page. The International Journal for Parasitology publishes the results of original research in all aspects of basic and applied parasitology, including all the fields covered by its Specialist Editors, and ranging from parasites and host-parasite relationships of intrinsic biological interest to those of social and economic importance in human and veterinary medicine and agriculture.