Dikicioglu Duygu, Oc Sebnem, Rash Bharat M, Dunn Warwick B, Pir Pınar, Kell Douglas B, Kirdar Betul, Oliver Stephen G
Cambridge Systems Biology Centre & Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK. sgo24@.cam.ac.uk
Mol Biosyst. 2014 Jan;10(1):93-102. doi: 10.1039/c2mb25512j.
Multiple drug resistance (MDR) in yeast is effected by two major superfamilies of membrane transporters: the major facilitator superfamily (MFS) and the ATP-binding cassette (ABC) superfamily. In the present work, we investigated the cellular responses to disruptions in both MFS (by deleting the transporter gene, QDR3) and ABC (by deleting the gene for the Pdr3 transcription factor) transporter systems by growing diploid homozygous deletion yeast strains in glucose- or ammonium-limited continuous cultures. The transcriptome and the metabolome profiles of these strains, as well as the flux distributions in the optimal solution space, reveal novel insights into the underlying mechanisms of action of QDR3 and PDR3. Our results show how cells rearrange their metabolism to cope with the problems that arise from the loss of these drug-resistance genes, which likely evolved to combat chemical attack from bacterial or fungal competitors. This is achieved through the accumulation of intracellular glucose, glycerol, and inorganic phosphate, as well as by repurposing genes that are known to function in other parts of metabolism in order to minimise the effects of toxic compounds.
酵母中的多重耐药性（MDR）受两个主要的膜转运蛋白超家族影响：主要易化子超家族（MFS）和ATP结合盒（ABC）超家族。在本研究中，我们通过在葡萄糖或铵限制的连续培养中培养二倍体纯合缺失酵母菌株，研究了细胞对MFS（通过缺失转运蛋白基因QDR3）和ABC（通过缺失Pdr3转录因子基因）转运系统破坏的反应。这些菌株的转录组和代谢组谱，以及最优解空间中的通量分布，揭示了对QDR3和PDR3潜在作用机制的新见解。我们的结果表明细胞如何重新安排其代谢以应对因这些耐药基因缺失而产生的问题，这些基因可能是为了对抗来自细菌或真菌竞争者的化学攻击而进化的。这是通过细胞内葡萄糖、甘油和无机磷酸盐的积累，以及通过重新利用已知在代谢其他部分起作用的基因来实现的，以便将有毒化合物的影响降至最低。
