Optknock: a bilevel programming framework for identifying gene knockout strategies for microbial strain optimization.
The advent of genome-scale models of metabolism has laid the foundation for the development of computational procedures for suggesting genetic manipulations that lead to overproduction. In this work, the computational OptKnock framework is introduced for suggesting gene deletion strategies leading to the overproduction of chemicals or biochemicals in E. coli. This is accomplished by ensuring that a drain towards growth resources (i.e., carbon, redox potential, and energy) must be accompanied, due to stoichiometry, by the production of a desired product. Computational results for gene deletions for succinate, lactate, and 1,3-propanediol (PDO) production are in good agreement with mutant strains published in the literature. While some of the suggested deletion strategies are straightforward and involve eliminating competing reaction pathways, many others suggest complex and nonintuitive mechanisms of compensating for the removed functionalities. Finally, the OptKnock procedure, by coupling biomass formation with chemical production, hints at a growth selection/adaptation system for indirectly evolving overproducing mutants.
Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Anthony P
AP
Burgard
Priti
P
Pharkya
Costas D
CD
Maranas
D000465:Algorithms; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D004926:Escherichia coli / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D024861:Genetic Enhancement / Q000379:methods*; D019344:Lactic Acid / Q000096:biosynthesis; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012984:Software; D019802:Succinic Acid / Q000378:metabolism
D009097:Multienzyme Complexes; D011409:Propylene Glycols; D011994:Recombinant Proteins; D019344:Lactic Acid; C041787:1,3-propanediol; D019802:Succinic Acid