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Applied and Environmental Microbiology, November 2005, p. 7122-7129, Vol. 71, No. 11
0099-2240/05/$08.00+0     doi:10.1128/AEM.71.11.7122-7129.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Engineering of Bacillus subtilis for Enhanced Total Synthesis of Folic Acid

T. Zhu,1,2 Z. Pan,3 N. Domagalski,1 R. Koepsel,3 M. M. Ataai,3 and M. M. Domach1*

Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213,1 Integrated Genomics Inc., Chicago, Illinois 60612,2 Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 152193

Received 7 March 2005/ Accepted 23 July 2005

We investigated whether the yield of the B vitamin folic acid could be elevated in Bacillus subtilis. Strategies for increasing the folic acid yield were investigated by employing computer-aided flux analysis and mutation. Controlling the activity of the enzyme pyruvate kinase by placing it under inducible control was one strategy devised to elevate yield while insuring that a rapid growth rate results. Other single mutation strategies included amplifying the expression of the genes in the folate operon and overexpressing the Escherichia coli aroH gene, which encodes 2-dehydro-3-deoxyphosphoheptonate aldolase. The latter could conceivably elevate the abundance of the folic acid precursor, para-aminobenzoic acid. Strains that combined two or more mutations were also constructed. Overall, a strain possessing inducible pyruvate kinase, overexpressed aroH, and increased transcription and translation of genes from the folic operon exhibited the best yield. The yield was eightfold higher than that displayed by the parent B. subtilis 168 strain.

* Corresponding author. Mailing address: Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213. Phone: (412) 268-2246. Fax: (412) 268-7139. E-mail: md0q{at}andrew.cmu.edu.

Applied and Environmental Microbiology, November 2005, p. 7122-7129, Vol. 71, No. 11
0099-2240/05/$08.00+0     doi:10.1128/AEM.71.11.7122-7129.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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