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.
Highlights
In metabolic networks, phenotypic responses to mutations that block the activity of nonessential biochemical reactions imply a fast rearrangement of fluxes
We studied three bacteria in the Enterobacteriaceae family: Escherichia coli (E. coli), Shigella sonnei (S. sonnei), and Salmonella enterica (S. enterica)
E. coli is the prototypical model organism for bacteria and, to put the results into perspective, we included in the study S. sonnei, known to present strong similarities with E. coli [16, 17], and S. enterica, a well differentiated bacterium [18]
Summary
Phenotypic responses to mutations that block the activity of nonessential biochemical reactions imply a fast rearrangement of fluxes. If a mutated enzymecoding gene or a disrupted reaction forms a synthetic lethal (SL) pair with a partner, meaning that their simultaneous deletion becomes lethal for the organism even though the individual removals are not [3,4,5,6,7], metabolic plasticity becomes essential to ensure viability. These synthetic lethalities provide the mutant with new vulnerabilities, exploitable for antimicrobial drug target identification [8] or, in the case of eukarya, for cancer therapy [9]
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