Research School of Biology, Australian National University, Canberra, Australian Capital Territory, Australia.
Biol Rev Camb Philos Soc. 2020 Apr;95(2):305-332. doi: 10.1111/brv.12565. Epub 2019 Nov 7.
Membrane transport proteins, also known as transporters, control the movement of ions, nutrients, metabolites, and waste products across the membranes of a cell and are central to its biology. Proteins of this type also serve as drug targets and are key players in the phenomenon of drug resistance. The malaria parasite has a relatively reduced transportome, with only approximately 2.5% of its genes encoding transporters. Even so, assigning functions and physiological roles to these proteins, and ascertaining their contributions to drug action and drug resistance, has been very challenging. This review presents a detailed critique and synthesis of the disruption phenotypes, protein subcellular localisations, protein functions (observed or predicted), and links to antimalarial drug resistance for each of the parasite's transporter genes. The breadth and depth of the gene disruption data are particularly impressive, with at least one phenotype determined in the parasite's asexual blood stage for each transporter gene, and multiple phenotypes available for 76% of the genes. Analysis of the curated data set revealed there to be relatively little redundancy in the Plasmodium transportome; almost two-thirds of the parasite's transporter genes are essential or required for normal growth in the asexual blood stage of the parasite, and this proportion increased to 78% when the disruption phenotypes available for the other parasite life stages were included in the analysis. These observations, together with the finding that 22% of the transportome is implicated in the parasite's resistance to existing antimalarials and/or drugs within the development pipeline, indicate that transporters are likely to serve, or are already serving, as drug targets. Integration of the different biological and bioinformatic data sets also enabled the selection of candidates for transport processes known to be essential for parasite survival, but for which the underlying proteins have thus far remained undiscovered. These include potential transporters of pantothenate, isoleucine, or isopentenyl diphosphate, as well as putative anion-selective channels that may serve as the pore component of the parasite's 'new permeation pathways'. Other novel insights into the parasite's biology included the identification of transporters for the potential development of antimalarial treatments, transmission-blocking drugs, prophylactics, and genetically attenuated vaccines. The syntheses presented herein set a foundation for elucidating the functions and physiological roles of key members of the Plasmodium transportome and, ultimately, to explore and realise their potential as therapeutic targets.
膜转运蛋白，也称为转运体，控制离子、营养物质、代谢物和废物在细胞的膜内外的运动，是细胞生物学的核心。这类蛋白质也是药物靶点，是耐药现象的关键参与者。疟原虫的转运蛋白组相对较少，只有大约 2.5%的基因编码转运体。即便如此，给这些蛋白质赋予功能和生理作用，并确定它们对药物作用和耐药性的贡献，一直是非常具有挑战性的。本文对疟原虫所有转运体基因的破坏表型、蛋白亚细胞定位、蛋白功能（观察到或预测到的）及其与抗疟药物耐药性的联系进行了详细的批判和综合。基因破坏数据的广度和深度尤其令人印象深刻，每个转运体基因在寄生虫的无性血期至少有一种表型被确定，76%的基因有多种表型。对已整理数据的分析表明，疟原虫的转运蛋白组中几乎没有冗余；几乎三分之二的寄生虫转运体基因对寄生虫无性血期的正常生长是必需的或必需的，当分析包括其他寄生虫生命阶段可用的破坏表型时，这一比例增加到 78%。这些观察结果，加上发现转运蛋白组中有 22%与寄生虫对现有抗疟药物和/或药物开发管道中的药物的耐药性有关，表明转运体可能已经或即将成为药物靶点。不同的生物学和生物信息数据集的整合还使得可以选择已知对寄生虫生存至关重要的转运过程的候选者，而这些转运过程的潜在蛋白质迄今仍未被发现。这包括泛酸、异亮氨酸或异戊烯二磷酸的潜在转运体，以及可能作为寄生虫“新渗透途径”的孔成分的阴离子选择性通道。对寄生虫生物学的其他新见解包括鉴定出用于开发抗疟治疗、传播阻断药物、预防药物和遗传减毒疫苗的转运体。本文提出的综合分析为阐明疟原虫转运蛋白组的关键成员的功能和生理作用奠定了基础，并最终探索和实现它们作为治疗靶点的潜力。
