The DSRS is an amazing and powerful new tool, the first example of a synthetic system that can dynamically regulate a metabolic pathway for improving production of fatty acid-based fuels and chemicals while the microbes are in the bioreactor,” says Jay Keasling, CEO of JBEI and one of the world’s foremost practitioners of synthetic biology, who led this research.
Keasling, who also serves as the Associate Laboratory Director for Biosciences at Lawrence Berkeley National Laboratory (Berkeley Lab) is the corresponding author of a paper describing this research in Nature Biotechnology. The paper is titled “Design of a dynamic sensor-regulator system for production of FAbased chemicals and fuels.” Co-authors are Fuzhong Zhang and James Carothers of JBEI’s Fuels Synthesis Division, which is directed by Keasling.
To create their DSRS, Zhang, Keasling and Carothers focused on a strain of Escherichia coli (E. coli) bacteria engineered at JBEI to produce diesel fuel directly from glucose. E. coli is a well-studied microorganism whose natural ability to synthesize fatty acids and exceptional amenability to genetic manipulation make it an ideal target for biofuels research. In this latest work, the JBEI researchers first developed biosensors for a key intermediate metabolite – fatty acyl-CoA – in the diesel biosynthetic pathway. They then developed a set of promoters (segments of DNA) that boost the expression of specific genes in response to cellular acyl-CoA levels. These synthetic promoters only become fully activated when both fatty acids and the inducer reagent known as “IPTG” are present.
“For a tightly regulated metabolic pathway to maximize product yields, it is essential that leaky gene expressions from promoters be eliminated,” Zhang says. “Since our hybrid promoters are repressed until induced by IPTG, and the induction levels can be tuned automatically by the FA/acyl-CoA level, they can be readily used to regulate production of biodiesel and other fatty acid-based chemicals.”
Introducing the DSRS into the biodiesel-producing strain of E.coli improved the stability of this strain and tripled the yield of fuel, reaching 28-percent of the theoretical maximum. With further refinements of the technique, yields should go even higher. The DSRS should also be applicable to the microbial production of other chemical products, both fatty acid-based and beyond.
“Given the large number of natural sensors available, our DSRS strategy can be extended to many other biosynthetic pathways to balance metabolism, increase product titers and yields, and stabilize production hosts,” Zhang says. “It should one day be possible to dynamically regulate any metabolic pathway, regardless of whether a natural sensor is available or not, to make microbial production of commodity chemicals and fuels competitive on a commercial scale.”
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