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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Validation of isoleucine utilization targets in Plasmodium falciparum
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Validation of isoleucine utilization targets in Plasmodium falciparum

机译：验证恶性疟原虫中异亮氨酸利用目标

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摘要

Intraerythrocytic malaria parasites can obtain nearly their entire amino acid requirement by degrading host cell hemoglobin. The sole exception is isoleucine, which is not present in adult human hemoglobin and must be obtained exogenously. We evaluated two compounds for their potential to interfere with isoleucine utilization. Mupirocin, a clinically used antibacterial, kills Plasmodium falciparum parasites at nanomolar concentrations. Thiaisoleucine, an isoleucine analog, also has antimalarial activity. To identify targets of the two compounds, we selected parasites resistant to either mupirocin or thiaisoleucine. Mutants were analyzed by genome-wide high-density tiling microarrays, DNA sequencing, and copy number variation analysis. The genomes of three independent mupirocin-resistant parasite clones had all acquired either amplifications encompassing or SNPs within the chromosomally encoded organellar (apicoplast) isoleucyl-tRNA synthetase. Thiaisoleucine-resistant parasites had a mutation in the cytoplasmic isoleucyl-tRNA synthetase. The role of this mutation in thiaisoleucine resistance was confirmed by allelic replacement. This approach is generally useful for elucidation of new targets in P. falciparum. Our study shows that isoleucine utilization is an essential pathway that can be targeted for antimalarial drug development.
机译：红细胞内疟原虫可通过降解宿主细胞血红蛋白获得几乎全部的氨基酸需求。唯一的例外是异亮氨酸，异亮氨酸不存在于成人血红蛋白中，必须从外源获得。我们评估了两种化合物干扰异亮氨酸利用的潜力。临床上使用的抗菌药莫匹罗星以纳摩尔浓度杀死恶性疟原虫。异亮氨酸类似物噻异亮氨酸也具有抗疟活性。为了鉴定这两种化合物的靶标，我们选择了对莫匹罗星或硫代异亮氨酸有抗性的寄生虫。通过全基因组高密度切片微阵列，DNA测序和拷贝数变异分析来分析突变体。三个独立的耐多匹罗星的寄生虫克隆的基因组均在染色体编码的细胞器（apicoplast）异亮氨酰-tRNA合成酶中获得了包含SNP的扩增。耐硫代异亮氨酸的寄生虫在胞质异亮氨酰-tRNA合成酶中具有突变。等位基因置换证实了该突变在硫代异亮氨酸抗性中的作用。该方法通常可用于阐明恶性疟原虫中的新靶标。我们的研究表明，异亮氨酸的利用是可用于抗疟药开发的重要途径。

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    Eva S. lstvan; Neekesh V. Dharia; Selina E. Bopp; llya Gluzman; Elizabeth A. Winzeler; Daniel E. Goldberg;

  • 作者单位

    Departments of Medicine and Microbiology and Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Cell Biology, ICND 202, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Cell Biology, ICND 202, The Scripps Research Institute, La Jolla, CA 92037;

    Departments of Medicine and Microbiology and Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110;

    Department of Cell Biology, ICND 202, The Scripps Research Institute, La Jolla, CA 92037;

    Departments of Medicine and Microbiology and Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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