合成致死突变体中的代谢可塑性:以更高代价维持生存。
Metabolic plasticity in synthetic lethal mutants: Viability at higher cost.
机构信息
Departament de Física de la Matèria Condensada, Universitat de Barcelona, Martí i Franquès 1, Barcelona, Spain.
Departament de Química Física, Universitat de Barcelona, Martí i Franquès 1, Barcelona, Spain.
出版信息
PLoS Comput Biol. 2018 Jan 30;14(1):e1005949. doi: 10.1371/journal.pcbi.1005949. eCollection 2018 Jan.
The most frequent form of pairwise synthetic lethality (SL) in metabolic networks is known as plasticity synthetic lethality. It occurs when the simultaneous inhibition of paired functional and silent metabolic reactions or genes is lethal, while the default of the functional partner is backed up by the activation of the silent one. Using computational techniques on bacterial genome-scale metabolic reconstructions, we found that the failure of the functional partner triggers a critical reorganization of fluxes to ensure viability in the mutant which not only affects the SL pair but a significant fraction of other interconnected reactions, forming what we call a SL cluster. Interestingly, SL clusters show a strong entanglement both in terms of reactions and genes. This strong overlap mitigates the acquired vulnerabilities and increased structural and functional costs that pay for the robustness provided by essential plasticity. Finally, the participation of coessential reactions and genes in different SL clusters is very heterogeneous and those at the intersection of many SL clusters could serve as supertargets for more efficient drug action in the treatment of complex diseases and to elucidate improved strategies directed to reduce undesired resistance to chemicals in pathogens.
代谢网络中最常见的成对合成致死(SL)形式被称为可塑性合成致死。当同时抑制配对的功能和沉默代谢反应或基因是致命的,而功能伙伴的默认情况由沉默伙伴的激活备份时,就会发生这种情况。我们使用细菌基因组尺度代谢重建的计算技术发现,功能伙伴的故障会触发通量的关键重排,以确保突变体的生存能力,这不仅会影响 SL 对,而且会影响很大一部分其他相互连接的反应,形成我们所谓的 SL 簇。有趣的是,SL 簇在反应和基因方面都表现出很强的纠缠性。这种强烈的重叠减轻了获得的脆弱性,并增加了结构和功能成本,以支付必需的可塑性提供的鲁棒性。最后,共必需反应和基因在不同的 SL 簇中的参与非常不均匀,并且那些在许多 SL 簇的交点处的反应和基因可以作为更有效的药物作用的超级靶点,用于治疗复杂疾病,并阐明改善的策略,以减少病原体中对化学品的不良耐药性。
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