title: Development of a Framework for Metabolic Pathway Analysis-Driven Strain Optimization Methods.
abstract: Genome-scale metabolic models (GSMMs) have become important assets for rational design of compound overproduction using microbial cell factories. Most computational strain optimization methods (CSOM) using GSMMs, while useful in metabolic engineering, rely on the definition of questionable cell objectives, leading to some bias. Metabolic pathway analysis approaches do not require an objective function. Though their use brings immediate advantages, it has mostly been restricted to small scale models due to computational demands. Additionally, their complex parameterization and lack of intuitive tools pose an important challenge towards making these widely available to the community. Recently, MCSEnumerator has extended the scale of these methods, namely regarding enumeration of minimal cut sets, now able to handle GSMMs. This work proposes a tool implementing this method as a Java library and a plugin within the OptFlux metabolic engineering platform providing a friendly user interface. A standard enumeration problem and pipeline applicable to GSMMs is proposed, making use by the community simpler. To highlight the potential of these approaches, we devised a case study for overproduction of succinate, providing a phenotype analysis of a selected strategy and comparing robustness with a selected solution from a bi-level CSOM.
authors.affiliation: Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.
authors.forename: Vitor
authors.initials: V
authors.lastname: Vieira
authors.affiliation: SilicoLife Lda., Rua do Canastreiro, 15, 4715-387, Braga, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Maia
authors.affiliation: Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rocha
authors.affiliation: Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal. mrocha@di.uminho.pt.
authors.forename: Miguel
authors.identifier: http://orcid.org/0000-0001-8439-8172
authors.initials: M
authors.lastname: Rocha
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D060847:Metabolic Engineering; D008954:Models, Biological
keywords: Constraint-based modeling; Metabolic engineering; Minimal cut sets; Pathway analysis; Strain optimization