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Title: Metabolic plasticity in synthetic lethal mutants: viability at higher cost
Author: Massucci, Francesco Alessandro
Sagués i Mestre, Francesc
Serrano Moral, Ma. Ángeles (María Ángeles)
Keywords: Gens
Biologia computacional
Computational biology
Issue Date: 30-Jan-2018
Publisher: Public Library of Science (PLoS)
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.
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It is part of: PLoS Computational Biology, 2018, vol. 14, num. 1, p. e1005949
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ISSN: 1553-734X
Appears in Collections:Articles publicats en revistes (Institut de Recerca en Sistemes Complexos (UBICS))
Articles publicats en revistes (Ciència dels Materials i Química Física)
Articles publicats en revistes (Física de la Matèria Condensada)

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