Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
Biochemistry (Mosc). 2020 Dec;85(12):1560-1569. doi: 10.1134/S0006297920120081.
Eukaryotic cells rely on multiple mechanisms to protect themselves from exogenous toxic compounds. For instance, cells can limit penetration of toxic molecules through the plasma membrane or sequester them within the specialized compartments. Plasma membrane transporters with broad substrate specificity confer multiple drug resistance (MDR) to cells. These transporters efflux toxic compounds at the cost of ATP hydrolysis (ABC-transporters) or proton influx (MFS-transporters). In our review, we discuss the possible costs of having an active drug-efflux system using yeast cells as an example. The pleiotropic drug resistance (PDR) subfamily ABC-transporters are known to constitutively hydrolyze ATP even without any substrate stimulation or transport across the membrane. Besides, some MDR-transporters have flippase activity allowing transport of lipids from inner to outer lipid layer of the plasma membrane. Thus, excessive activity of MDR-transporters can adversely affect plasma membrane properties. Moreover, broad substrate specificity of ABC-transporters also suggests the possibility of unintentional efflux of some natural metabolic intermediates from the cells. Furthermore, in some microorganisms, transport of quorum-sensing factors is mediated by MDR transporters; thus, overexpression of the transporters can also disturb cell-to-cell communications. As a result, under normal conditions, cells keep MDR-transporter genes repressed and activate them only upon exposure to stresses. We speculate that exploiting limitations of the drug-efflux system is a promising strategy to counteract MDR in pathogenic fungi.
真核细胞依赖多种机制来保护自己免受外源有毒化合物的侵害。例如，细胞可以限制有毒分子通过质膜的渗透，或者将它们隔离在专门的隔室中。具有广泛底物特异性的质膜转运蛋白赋予细胞多重耐药性（MDR）。这些转运蛋白以 ATP 水解（ABC 转运蛋白）或质子内流（MFS 转运蛋白）为代价将有毒化合物排出细胞外。在我们的综述中，我们以酵母细胞为例讨论了拥有活性药物外排系统的可能代价。多药耐药（PDR）亚家族 ABC 转运蛋白已知即使没有任何底物刺激或跨膜运输，也会持续水解 ATP。此外，一些 MDR 转运蛋白具有翻转酶活性，允许将脂质从质膜的内脂质层转运到外脂质层。因此，MDR 转运蛋白的过度活性会对质膜性质产生不利影响。此外，ABC 转运蛋白的广泛底物特异性也表明，一些天然代谢中间产物可能会意外地从细胞中排出。此外，在一些微生物中，群体感应因子的运输是由 MDR 转运蛋白介导的；因此，转运蛋白的过度表达也会干扰细胞间通讯。因此，在正常情况下，细胞会抑制 MDR 转运蛋白基因的表达，并仅在暴露于应激时才激活它们。我们推测，利用药物外排系统的局限性是对抗致病性真菌 MDR 的一种有前途的策略。
