Genome-scale modeling enables metabolic engineering of Saccharomyces cerevisiae for succinic acid production

Rasmus Agren, José Manuel Otero, Jens Nielsen

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Abstract

In this work, we describe the application of a genome-scale metabolic model and flux balance analysis for the prediction of succinic acid overproduction strategies in Saccharomyces cerevisiae. The top three single gene deletion strategies, Δmdh1, Δoac1, and Δdic1, were tested using knock-out strains cultivated anaerobically on glucose, coupled with physiological and DNA microarray characterization. While Δmdh1 and Δoac1 strains failed to produce succinate, Δdic1 produced 0.02 C-mol/C-mol glucose, in close agreement with model predictions (0.03 C-mol/C-mol glucose). Transcriptional profiling suggests that succinate formation is coupled to mitochondrial redox balancing, and more specifically, reductive TCA cycle activity. While far from industrial titers, this proof-of-concept suggests that in silico predictions coupled with experimental validation can be used to identify novel and non-intuitive metabolic engineering strategies.

Original languageEnglish
JournalJournal of Industrial Microbiology and Biotechnology
Volume40
Issue number7
Pages (from-to)735-747
ISSN1367-5435
DOIs
Publication statusPublished - 2013
Externally publishedYes

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