From the ‡Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109.
§Department of Global Health, University of Washington, Seattle, Washington 98195.
Mol Cell Proteomics. 2018 Jan;17(1):111-120. doi: 10.1074/mcp.RA117.000088. Epub 2017 Oct 27.
Effective malaria control and elimination in hyperendemic areas of the world will require treatment of the () blood stage that causes disease as well as the gametocyte stage that is required for transmission from humans to the mosquito vector. Most currently used therapies do not kill gametocytes, a highly specialized, non-replicating sexual parasite stage. Further confounding next generation drug development against is the unknown metabolic state of the gametocyte and the lack of known biochemical activity for most parasite gene products in general. Here, we take a systematic activity-based proteomics approach to survey the activity of the large and druggable ATPase family in replicating blood stage asexual parasites and transmissible, non-replicating sexual gametocytes. ATPase activity broadly changes during the transition from asexual schizonts to sexual gametocytes, indicating altered metabolism and regulatory roles of ATPases specific for each lifecycle stage. We further experimentally confirm existing annotation and predict ATPase function for 38 uncharacterized proteins. By mapping the activity of ATPases associated with gametocytogenesis, we assign biochemical activity to a large number of uncharacterized proteins and identify new candidate transmission blocking targets.
要在世界上高度流行疟疾的地区实现有效的疟疾控制和消除，就需要治疗引起疾病的（）红细胞期，以及人类传播给蚊子媒介所需的配子体期。大多数目前使用的疗法不能杀死配子体，配子体是一种高度特化的、非复制的有性寄生虫阶段。进一步阻碍下一代针对（）的药物研发的是配子体未知的代谢状态，以及一般来说大多数寄生虫基因产物缺乏已知的生化活性。在这里，我们采用系统的基于活性的蛋白质组学方法来检测复制性血期无性体和可传播的非复制性有性配子体中大量且可成药的 ATP 酶家族的活性。ATP 酶活性在从无性裂殖体到有性配子体的转变过程中广泛变化，表明代谢发生改变，以及针对每个生命周期阶段的 ATP 酶的调节作用。我们进一步通过实验验证了 38 个未表征蛋白的现有注释，并预测了它们的 ATP 酶功能。通过对配子体发生相关的 ATP 酶的活性进行作图，我们将生化活性分配给大量未表征的蛋白，并确定了新的候选传播阻断靶标。
