Systems Microbiology Laboratory, Department of Biology, Faculty of Science, University of Chile, Chile.
Systems Microbiology Laboratory, Department of Biology, Faculty of Science, University of Chile, Chile; Department of Ecology, Faculty of Science, University of Chile, Chile.
Biochim Biophys Acta Gen Subj. 2017 Apr;1861(4):871-883. doi: 10.1016/j.bbagen.2017.01.007. Epub 2017 Jan 7.
Polyphosphate (polyP) is a linear biopolymer found in all living cells. In bacteria, mutants lacking polyphosphate kinase 1 (PPK1), the enzyme responsible for synthesis of most polyP, have many structural and functional defects. However, little is known about the causes of these pleiotropic alterations. The link between ppk1 deletion and those numerous phenotypes observed can be the result of complex molecular interactions that can be elucidated via a systems biology approach.
By integrating different omics levels (transcriptome, proteome and phenome), we described the functioning of various metabolic pathways among Escherichia coli polyphosphate mutant strains (Δppk1, Δppx, and ΔpolyP). Bioinformatic analyses reveal the complex metabolic and regulatory bases of the phenotypes unique to polyP mutants.
Our results suggest that during polyP deficiency (Δppk1 mutant), metabolic pathways needed for energy supply are up-regulated, including fermentation, aerobic and anaerobic respiration. Transcriptomic and q-proteomic contrasting changes between Δppk1 and Δppx mutant strains were observed in those central metabolic pathways and confirmed by using Phenotypic microarrays. In addition, our results suggest a regulatory connection between polyP, second messenger metabolism, alternative Sigma/Anti-Sigma factors and type-II toxin-antitoxin (TA) systems.
We suggest a broader role for polyP via regulation of ATP-dependent proteolysis of type II toxin-antitoxin system and alternative Sigma/Anti-Sigma factors, that could explain the multiple structural and functional deficiencies described due to alteration of polyP metabolism.
Understanding the interplay of polyP in bacterial metabolism using a systems biology approach can help to improve design of novel antimicrobials toward pathogens.
聚磷酸盐（polyP）是一种存在于所有活细胞中的线性生物聚合物。在细菌中，缺乏负责合成大多数 polyP 的酶——多聚磷酸激酶 1（PPK1）的突变体有许多结构和功能缺陷。然而，对于这些多效性改变的原因知之甚少。ppk1 缺失与观察到的许多表型之间的联系可能是复杂的分子相互作用的结果，可以通过系统生物学方法来阐明。
通过整合不同的组学水平（转录组、蛋白质组和表型组），我们描述了大肠杆菌聚磷酸盐突变株（Δppk1、Δppx 和 ΔpolyP）中各种代谢途径的功能。生物信息学分析揭示了 polyP 突变体独特表型的复杂代谢和调控基础。
我们的结果表明，在 polyP 缺乏（Δppk1 突变体）时，需要能量供应的代谢途径被上调，包括发酵、需氧和厌氧呼吸。在中央代谢途径中观察到Δppk1 和 Δppx 突变株之间的转录组和 q 蛋白质组的对比变化，并通过使用表型微阵列进行了验证。此外，我们的结果表明，polyP 与第二信使代谢、替代 Sigma/反 Sigma 因子和 II 型毒素-抗毒素（TA）系统之间存在调节连接。
我们通过调节 II 型毒素-抗毒素系统和替代 Sigma/反 Sigma 因子的 ATP 依赖性蛋白水解，提出了 polyP 的更广泛作用，这可以解释由于 polyP 代谢改变而描述的多种结构和功能缺陷。
使用系统生物学方法理解 polyP 在细菌代谢中的相互作用，可以帮助设计针对病原体的新型抗菌药物。
