Development of a Framework for Metabolic Pathway Analysis-Driven Strain Optimization Methods

Vitor Vieira, Paulo Maia, Isabel Rocha, Miguel Rocha
2017 Interdisciplinary Sciences Computational Life Sciences  
comparing robustness with a selected solution from a bilevel CSOM. Keywords Constraint-based modeling · Metabolic engineering · Pathway analysis · Minimal cut sets · Strain optimization Abbreviations List of Enzymes ACOAH Acetyl-CoA hydrolase ATPS atp synthase G6PDH Glucose 6-phosphate dehydrogenase GAPD Glyceraldehyde 3-phosphate dehydrogenase NADH2 NADH dehydrogenase PGK Phosphoglycerate kinase PYRDC Pyruvate decarboxylase SUCD2 Succinate dehydrogenase iron-sulfur protein SUCD3 Succinate
more » ... rogenase cytochrome b SUCD Succinate dehydrogenase complex List of Metabolites − kg Alpha-ketoglutarate atp Adenosine triphosphate dhap Dihydroxyacetone phosphate gaba Gamma-aminobutyrate nadh Nicotinamide adenine dinucleotide (reduced) nadph Nicotinamide adenine dinucleotide phosphate (reduced) nadp + Nicotinamide adenine dinucleotide phosphate (oxidized) 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 Electronic supplementary material The online version of this article (
doi:10.1007/s12539-017-0218-7 pmid:28238112 fatcat:6yfi4pqmvzecfgmtb2ot55azoi