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Applied and Environmental Microbiology, September 2009, p. 5831-5839, Vol. 75, No. 18
0099-2240/09/$08.00+0     doi:10.1128/AEM.00270-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Increased Malonyl Coenzyme A Biosynthesis by Tuning the Escherichia coli Metabolic Network and Its Application to Flavanone Production{triangledown} ,{dagger}

Zachary L. Fowler, William W. Gikandi, and Mattheos A. G. Koffas*

Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, 303 Clifford C. Furnas Hall, Buffalo, New York 14260

Received 3 February 2009/ Accepted 18 July 2009

Identification of genetic targets able to bring about changes to the metabolite profiles of microorganisms continues to be a challenging task. We have independently developed a cipher of evolutionary design (CiED) to identify genetic perturbations, such as gene deletions and other network modifications, that result in optimal phenotypes for the production of end products, such as recombinant natural products. Coupled to an evolutionary search, our method demonstrates the utility of a purely stoichiometric network to predict improved Escherichia coli genotypes that more effectively channel carbon flux toward malonyl coenzyme A (CoA) and other cofactors in an effort to generate recombinant strains with enhanced flavonoid production capacity. The engineered E. coli strains were constructed first by the targeted deletion of native genes predicted by CiED and then second by incorporating selected overexpressions, including those of genes required for the coexpression of the plant-derived flavanones, acetate assimilation, acetyl-CoA carboxylase, and the biosynthesis of coenzyme A. As a result, the specific flavanone production from our optimally engineered strains was increased by over 660% for naringenin (15 to 100 mg/liter/optical density unit [OD]) and by over 420% for eriodictyol (13 to 55 mg/liter/OD).

* Corresponding author. Mailing address: Department of Chemical and Biological Engineering, University at Buffalo, State University of New York, 303 Clifford C. Furnas Hall, Buffalo, NY 14260. Phone: (716) 645-1198. Fax: (716) 645-3822. E-mail: mkoffas{at}eng.buffalo.edu

{triangledown} Published ahead of print on 24 July 2009.

{dagger} Supplemental material for this article may be found at http://aem.asm.org/.

Applied and Environmental Microbiology, September 2009, p. 5831-5839, Vol. 75, No. 18
0099-2240/09/$08.00+0     doi:10.1128/AEM.00270-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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