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OptDesign: Identifying Optimum Design Strategies in Strain Engineering for Biochemical Production.

ABSTRACT: Computational tools have been widely adopted for strain optimization in metabolic engineering, contributing to numerous success stories of producing industrially relevant biochemicals. However, most of these tools focus on single metabolic intervention strategies (either gene/reaction knockout or amplification alone) and rely on hypothetical optimality principles (e.g., maximization of growth) and precise gene expression (e.g., fold changes) for phenotype prediction. This paper introduces OptDesign, a new two-step strain design strategy. In the first step, OptDesign selects regulation candidates that have a noticeable flux difference between the wild type and production strains. In the second step, it computes optimal design strategies with limited manipulations (combining regulation and knockout), leading to high biochemical production. The usefulness and capabilities of OptDesign are demonstrated for the production of three biochemicals in Escherichia coli using the latest genome-scale metabolic model iML1515, showing highly consistent results with previous studies while suggesting new manipulations to boost strain performance. The source code is available at https://github.com/chang88ye/OptDesign.

SUBMITTER: Jiang S

PROVIDER: S-EPMC9016760 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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OptDesign: Identifying Optimum Design Strategies in Strain Engineering for Biochemical Production.

Jiang Shouyong S Otero-Muras Irene I Banga Julio R JR Wang Yong Y Kaiser Marcus M Krasnogor Natalio N

ACS synthetic biology 20220407 4

Computational tools have been widely adopted for strain optimization in metabolic engineering, contributing to numerous success stories of producing industrially relevant biochemicals. However, most of these tools focus on single metabolic intervention strategies (either gene/reaction knockout or amplification alone) and rely on hypothetical optimality principles (e.g., maximization of growth) and precise gene expression (e.g., fold changes) for phenotype prediction. This paper introduces OptDes ...[more]

PMID: 35389631

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Project description:Yarrowia lipolytica is a non-pathogenic, dimorphic and strictly aerobic yeast species. Owing to its distinctive physiological features and metabolic characteristics, this unconventional yeast is not only a good model for the study of the fundamental nature of fungal differentiation but is also a promising microbial platform for biochemical production and various biotechnological applications, which require extensive genetic manipulations. However, genetic manipulations of Y. lipolytica have been limited due to the lack of an efficient and stable genetic transformation system as well as very high rates of non-homologous recombination that can be mainly attributed to the KU70 gene. Here, we report an easy and rapid protocol for the efficient genetic transformation and for gene deletion in Y. lipolytica Po1g. First, a protocol for the efficient transformation of exogenous DNA into Y. lipolytica Po1g was established. Second, to achieve the enhanced double-crossover homologous recombination rate for further deletion of target genes, the KU70 gene was deleted by transforming a disruption cassette carrying 1 kb homology arms. Third, to demonstrate the enhanced gene deletion efficiency after deletion of the KU70 gene, we individually deleted 11 target genes encoding alcohol dehydrogenase and alcohol oxidase using the same procedures on the KU70 knockout platform strain. It was observed that the rate of precise homologous recombination increased substantially from less than 0.5% for deletion of the KU70 gene in Po1g to 33%-71% for the single gene deletion of the 11 target genes in Po1g KU70Δ. A replicative plasmid carrying the hygromycin B resistance marker and the Cre/LoxP system was constructed, and the selection marker gene in the yeast knockout strains was eventually removed by expression of Cre recombinase to facilitate multiple rounds of targeted genetic manipulations. The resulting single-gene deletion mutants have potential applications in biofuel and biochemical production.

Dataset Information

OptDesign: Identifying Optimum Design Strategies in Strain Engineering for Biochemical Production.

Publications

OptDesign: Identifying Optimum Design Strategies in Strain Engineering for Biochemical Production.

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