Metabolic plasticity in synthetic lethal mutants: Viability at higher cost

PLoS Comput Biol. 2018 Jan 30;14(1):e1005949. doi: 10.1371/journal.pcbi.1005949. eCollection 2018 Jan.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / metabolism
  • Cluster Analysis
  • Computational Biology*
  • Culture Media
  • Escherichia coli / genetics
  • Genome
  • Genome, Bacterial
  • Glucose / chemistry
  • Metabolic Networks and Pathways*
  • Models, Theoretical
  • Oxygen Consumption
  • Salmonella enterica
  • Shigella sonnei
  • Synthetic Lethal Mutations*

Substances

  • Culture Media
  • Glucose

Grants and funding

FAM acknowledges financial support from the grant PTQ-14-06718 by the Torres Quevedo programme of the MINECO. FS acknowledges support from MINECO projects no. FIS2013-41144P and FIS2016-78507-C2-1-P (AEI/FEDER, UE). MAS acknowledges support from the James S. McDonnell Foundation Scholar Award in Complex Systems; MINECO projects no. FIS2013-47282-C2-1-P and no. FIS2016-76830-C2-2-P (AEI/FEDER, UE); and the Generalitat de Catalunya grant no. 2014SGR608. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.