Author:
Guzmán Gabriela I.,Sandberg Troy E.,LaCroix Ryan A.,Nyerges Akos,Papp Henrietta,Raad Markus de,King Zachary A.,Northen Trent R.,Notebaart Richard A.,Pál Csaba,Palsson Bernhard O.,Papp Balázs,Feist Adam M.
Abstract
AbstractEvidence suggests that novel enzyme functions evolved from low-level promiscuous activities in ancestral enzymes. Yet, the evolutionary dynamics and physiological mechanisms of how such side activities contribute to systems-level adaptations are poorly understood. Furthermore, it remains untested whether knowledge of an organism’s promiscuous reaction set (‘underground metabolism’) can aid in forecasting the genetic basis of metabolic adaptations. Here, we employ a computational model of underground metabolism and laboratory evolution experiments to examine the role of enzyme promiscuity in the acquisition and optimization of growth on predicted non-native substrates inE. coliK-12 MG1655. After as few as 20 generations, the evolving populations repeatedly acquired the capacity to grow on five predicted novel substrates–D-lyxose, D-2-deoxyribose, D-arabinose, m-tartrate, and monomethyl succinate–none of which could support growth in wild-type cells. Promiscuous enzyme activities played key roles in multiple phases of adaptation. Altered promiscuous activities not only established novel high-efficiency pathways, but also suppressed undesirable metabolic routes. Further, structural mutations shifted enzyme substrate turnover rates towards the new substrate while retaining a preference for the primary substrate. Finally, genes underlying the phenotypic innovations were accurately predicted by genome-scale model simulations of metabolism with enzyme promiscuity. Computational approaches will be essential to synthesize the complex role of promiscuous activities in applied biotechnology and in models of evolutionary adaptation.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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