Genome-scale modeling using flux ratio constraints to enable metabolic engineering of clostridial metabolism in silico

McAnulty, Michael J.; Yen, Jiun Y.; Freedman, Benjamin G.; Senger, Ryan S.

Genome-scale modeling using flux ratio constraints to enable metabolic engineering of clostridial metabolism in silico

dc.contributor.author	McAnulty, Michael J.	en
dc.contributor.author	Yen, Jiun Y.	en
dc.contributor.author	Freedman, Benjamin G.	en
dc.contributor.author	Senger, Ryan S.	en
dc.contributor.department	Biological Systems Engineering	en
dc.date.accessioned	2012-11-12T20:03:18Z	en
dc.date.available	2012-11-12T20:03:18Z	en
dc.date.issued	2012-05-14	en
dc.date.updated	2012-11-12T20:03:19Z	en
dc.description.abstract	Background Genome-scale metabolic networks and flux models are an effective platform for linking an organism genotype to its phenotype. However, few modeling approaches offer predictive capabilities to evaluate potential metabolic engineering strategies in silico. Results A new method called “flux balance analysis with flux ratios (FBrAtio)” was developed in this research and applied to a new genome-scale model of Clostridium acetobutylicum ATCC 824 (iCAC490) that contains 707 metabolites and 794 reactions. FBrAtio was used to model wild-type metabolism and metabolically engineered strains of C. acetobutylicum where only flux ratio constraints and thermodynamic reversibility of reactions were required. The FBrAtio approach allowed solutions to be found through standard linear programming. Five flux ratio constraints were required to achieve a qualitative picture of wild-type metabolism for C. acetobutylicum for the production of: (i) acetate, (ii) lactate, (iii) butyrate, (iv) acetone, (v) butanol, (vi) ethanol, (vii) CO2 and (viii) H2. Results of this simulation study coincide with published experimental results and show the knockdown of the acetoacetyl-CoA transferase increases butanol to acetone selectivity, while the simultaneous over-expression of the aldehyde/alcohol dehydrogenase greatly increases ethanol production. Conclusions FBrAtio is a promising new method for constraining genome-scale models using internal flux ratios. The method was effective for modeling wild-type and engineered strains of C. acetobutylicum.	en
dc.description.version	Published version	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	BMC Systems Biology. 2012 May 14;6(1):42	en
dc.identifier.doi	https://doi.org/10.1186/1752-0509-6-42	en
dc.identifier.uri	http://hdl.handle.net/10919/19069	en
dc.language.iso	en	en
dc.rights	Creative Commons Attribution 4.0 International	en
dc.rights.holder	Michael J McAnulty et al.; licensee BioMed Central Ltd.	en
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	en
dc.title	Genome-scale modeling using flux ratio constraints to enable metabolic engineering of clostridial metabolism in silico	en
dc.title.serial	BMC Systems Biology	en
dc.type	Article - Refereed	en
dc.type.dcmitype	Text	en