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Bioprocess Biosyst Eng. 2013 Jan;36(1):45-56. doi: 10.1007/s00449-012-0760-y. Epub 2012 Jun 1.

Metabolic pathway analysis and kinetic studies for production of nattokinase in Bacillus subtilis.

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Biochemical Engineering and Pilot Plant Research and Development Unit, King Mongkut's University of Technology Thonburi, 49 Soi Tientalay 25, Bangkhuntien-Chaytalay Rd., Thakhum, Bangkhuntien, Bangkok 10150, Thailand.


We have constructed a reaction network model of Bacillus subtilis. The model was analyzed using a pathway analysis tool called elementary mode analysis (EMA). The analysis tool was used to study the network capabilities and the possible effects of altered culturing conditions on the production of a fibrinolytic enzyme, nattokinase (NK) by B. subtilis. Based on all existing metabolic pathways, the maximum theoretical yield for NK synthesis in B. subtilis under different substrates and oxygen availability was predicted and the optimal culturing condition for NK production was identified. To confirm model predictions, experiments were conducted by testing these culture conditions for their influence on NK activity. The optimal culturing conditions were then applied to batch fermentation, resulting in high NK activity. The EMA approach was also applied for engineering B. subtilis metabolism towards the most efficient pathway for NK synthesis by identifying target genes for deletion and overexpression that enable the cell to produce NK at the maximum theoretical yield. The consistency between experiments and model predictions proves the feasibility of EMA being used to rationally design culture conditions and genetic manipulations for the efficient production of desired products.

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