Enzyme promiscuity shapes evolutionary innovation and optimization
Enzyme promiscuity shapes evolutionary innovation and optimization
Abstract Evidence 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 in E. coli K-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.
Feist Adam M.、Guzm¨￠n Gabriela I.、Notebaart Richard A.、P¨￠l Csaba、King Zachary A.、Papp Henrietta、Sandberg Troy E.、Nyerges ¨￠kos、LaCroix Ryan A.、Northen Trent R.、Palsson Bernhard O.、Papp Bal¨￠zs、de Raad Markus
Department of Bioengineering, University of California||Novo Nordisk Foundation Center for Biosustainability, Technical University of DenmarkDepartment of Bioengineering, University of CaliforniaLaboratory of Food Microbiology, Wageningen University and ResearchSynthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of SciencesDepartment of Bioengineering, University of CaliforniaSynthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of SciencesDepartment of Bioengineering, University of CaliforniaSynthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of SciencesDepartment of Bioengineering, University of CaliforniaEnvironmental Genomics and Systems Biology Division, Lawrence Berkeley National LaboratoryDepartment of Bioengineering, University of California||Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark||Department of Pediatrics, University of CaliforniaSynthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of SciencesEnvironmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory
生物科学理论、生物科学方法生物科学研究方法、生物科学研究技术生物化学
adaptive evolutionenzyme promiscuitysystems biologygenome-scale modeling
Feist Adam M.,Guzm¨￠n Gabriela I.,Notebaart Richard A.,P¨￠l Csaba,King Zachary A.,Papp Henrietta,Sandberg Troy E.,Nyerges ¨￠kos,LaCroix Ryan A.,Northen Trent R.,Palsson Bernhard O.,Papp Bal¨￠zs,de Raad Markus.Enzyme promiscuity shapes evolutionary innovation and optimization[EB/OL].(2025-03-28)[2025-07-16].https://www.biorxiv.org/content/10.1101/310946.点此复制
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