Abstract

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.

中文翻译：

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在正常条件下，多种耐药转运蛋白会干扰细胞功能吗？

摘要

真核细胞依靠多种机制来保护自己免受外源性有毒化合物的侵害。例如，细胞可以限制有毒分子穿透质膜或将其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种耐药性（MDR）。这些转运蛋白以ATP水解（ABC转运蛋白）或质子涌入（MFS转运蛋白）为代价排出有毒化合物。在我们的综述中，我们讨论使用酵母细胞作为示例的具有活性药物外排系统的可能成本。已知，即使没有任何底物刺激或跨膜转运，多效性耐药性（PDR）亚家族ABC转运蛋白也能组成性地水解ATP。除了，一些MDR转运蛋白具有脂酶活性，允许脂质从质膜的内脂质层向外脂质层转运。因此，MDR转运蛋白的过度活性会不利地影响质膜特性。而且，ABC转运蛋白的广泛的底物特异性还暗示了细胞中某些天然代谢中间体意外流出的可能性。此外，在某些微生物中，群体感应因子的转运是由MDR转运蛋白介导的。因此，转运蛋白的过表达也会干扰细胞间的通信。结果，在正常条件下，细胞使MDR-转运蛋白基因受到抑制，仅在受到压力时才激活它们。我们推测，利用药物外排系统的局限性是对抗病原性真菌中耐多药耐药性的一种有前途的策略。