4.7 Article

Improving heterologous polyketide production in Escherichia coli by transporter engineering

Journal

APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
Volume 99, Issue 20, Pages 8691-8700

Publisher

SPRINGER
DOI: 10.1007/s00253-015-6718-7

Keywords

Efflux pump; Polyketide erythromycin; Escherichia coli; Heterologous production; Transcriptional regulator

Funding

  1. National Basic Research Program of China (973 Program) [2012CB721104]
  2. National High Technology Research and Development Program (863 Program) [2012AA02A701]
  3. National Natural Science Foundation of China [31170101]
  4. Shanghai Science and Technology Commission [14JC1406900]
  5. Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences [2014KIP104]

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Expelling heterologous compounds out of hosts by transporters is a potential strategy to enhance product titers in microbial cell factories. In this work, to increase heterologous polyketide 6-deoxyerythronolide B (6dEB, erythromycin precursor) production, tripartite multidrug efflux pumps MacAB-TolC, AcrAB-TolC, MdtEF-TolC, and MexAB-OprM were modulated in a 6dEB production strain. Compared with the control, overexpression of a single component of efflux pumps (except oprM) repressed 6dEB production, but modulation of two components MacA and MacB or the complete pumps MacAB-TolC and MdtEF-TolC significantly improved 6dEB titer by 100 +/- A 11, 118 +/- A 54, and 98 +/- A 12 %, respectively. In addition, to avoid the challenging fine-tuning components of pumps, the transcriptional regulators of efflux pumps were modulated to improve the 6dEB production. Overexpression of RpoH (activator of MdtEF-TolC) and EvgA (activator of EmrKY-TolC and AcrAD-TolC) strongly increased 6dEB titer by 152 +/- A 54 and 142 +/- A 85 %, respectively. This is the first report of transporter engineering for improving heterologous polyketide production in Escherichia coli. Our results provide an effective strategy for improving the yield of the heterologous products in chassis cell.

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