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恶性疟原虫双功能葡萄糖-6-磷酸脱氢酶-6-磷酸葡萄糖酸内酯酶的瞬时沉默

Transient silencing of Plasmodium falciparum bifunctional glucose-6-phosphate dehydrogenase- 6-phosphogluconolactonase.

作者信息

Crooke Almudena, Diez Amalia, Mason Philip J, Bautista José M

机构信息

Department of Biochemistry and Molecular Biology IV, Universidad Complutense de Madrid, Facultad de Veterinaria, Madrid, Spain.

出版信息

FEBS J. 2006 Apr;273(7):1537-46. doi: 10.1111/j.1742-4658.2006.05174.x.

Abstract

The bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (G6PD-6PGL) found in Plasmodium falciparum has unique structural and functional characteristics restricted to this genus. This study was designed to examine the effects of RNA-mediated PfG6PD-6PGL gene silencing in cultures of P. falciparum on the expression of parasite antioxidant defense genes at the transcription level. The highest degree of G6PD-6PGL silencing achieved was 86% at the mRNA level, with a recovery to almost normal levels within 24 h, indicating only transient diminished expression of the PfG6PD-6PGL gene. PfG6PD-6PGL silencing caused arrest of the trophozoite stage and enhanced gametocyte formation. In addition, an immediate transcriptional response was shown by thioredoxin reductase suggesting that P. falciparum G6PD-6PGL plays a physiological role in the specific response of the parasite to intracellullar oxidative stress. P. falciparum transfection with an empty DNA vector also promoted intracellular stress, as determined by mRNA up-regulation of antioxidant genes. Collectively, our findings point to an important role for this enzyme in the parasite's infection cycle. The different characteristics of G6PD-6PGL with respect to its homologue in the host make it an ideal target for therapeutic strategies.

摘要

在恶性疟原虫中发现的双功能酶葡萄糖-6-磷酸脱氢酶-6-磷酸葡萄糖酸内酯酶(G6PD-6PGL)具有仅限于该属的独特结构和功能特征。本研究旨在检测RNA介导的PfG6PD-6PGL基因沉默对恶性疟原虫培养物中寄生虫抗氧化防御基因转录水平表达的影响。在mRNA水平上实现的G6PD-6PGL沉默的最高程度为86%,且在24小时内恢复到几乎正常水平,表明PfG6PD-6PGL基因的表达仅短暂减少。PfG6PD-6PGL沉默导致滋养体阶段停滞并增强配子体形成。此外,硫氧还蛋白还原酶显示出即时转录反应,表明恶性疟原虫G6PD-6PGL在寄生虫对细胞内氧化应激的特异性反应中发挥生理作用。用空DNA载体转染恶性疟原虫也会促进细胞内应激,这通过抗氧化基因的mRNA上调来确定。总体而言,我们的研究结果表明该酶在寄生虫感染周期中起重要作用。G6PD-6PGL与其宿主同源物相比的不同特征使其成为治疗策略的理想靶点。

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