Haloacid Dehalogenase Proteins: Novel Mediators of Metabolic Plasticity in Plasmodium falciparum.
Haloacid Dehalogenase Proteins: Novel Mediators of Metabolic Plasticity in Plasmodium falciparum.
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DOI：
10.1177/1178636119848435
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发表时间：
2019-01-01
影响因子：
--
通讯作者：
Odom John, Audrey R
中科院分区：
文献类型：
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作者：
Frasse, Philip M;Odom John, Audrey R
广泛的抗疟药物耐药性促使人们需要新的治疗方法和更好地了解疟疾寄生虫的生物学。为此，类异戊二烯生物合成抑制剂磷咪霉素已被用于探测疟疾寄生虫恶性疟原虫的代谢调节。卤酸脱卤酶（HAD）超家族成员HAD 2的遗传变化赋予了对磷霉素的抗性，代价是适应性降低。在没有磷酰胺霉素的情况下，寄生虫获得了磷酸果糖激酶的突变，恢复了生长和磷酰胺霉素的敏感性，从而揭示了一个有趣的例子可塑性的核心糖酵解过程。此外，这项研究标志着第二次报告的HAD超家族蛋白调节代谢稳态的恶性疟原虫。卤酸脱卤酶分布在生活的各个领域，并且越来越多地被发现影响恶性疟原虫的中心碳代谢和药物敏感性。研究HAD超家族成员调节代谢的机制可能有助于了解顶复门寄生虫和其他生物体中代谢网络的连接方式，并可能指导未来的治疗工作。
Widespread antimalarial drug resistance has prompted the need for new therapeutics and greater understanding of malaria parasite biology. To this end, the isoprenoid biosynthesis inhibitor fosmidomycin has been used to probe the metabolic regulation in the malaria parasite, Plasmodium falciparum. Genetic changes in the haloacid dehalogenase (HAD) superfamily member HAD2 conferred resistance to fosmidomycin, at the cost of decreased fitness. In the absence of fosmidomycin, parasites gained mutations to phosphofructokinase that restored growth and fosmidomycin sensitivity, thus revealing an intriguing example of plasticity in a core glycolytic process. Moreover, this study marks a second report of a HAD superfamily protein-modulating metabolic homeostasis in P falciparum parasites. Haloacid dehalogenase enzymes are distributed across all domains of life and have increasingly been found to influence central carbon metabolism and drug sensitivity in P falciparum. Investigating the mechanisms by which HAD superfamily members modulate metabolism may shed light on how metabolic networks are connected in apicomplexan parasites and other organisms and may guide future therapeutic endeavors.