Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Less Toxic Metabolites, More Chemical Product

Published: Thursday, October 31, 2013
Last Updated: Thursday, October 31, 2013
Bookmark and Share
The first dynamic regulatory system that prevents the build-up of toxic metabolites in engineered microbes has been reported.

The JBEI researchers used their system to double the production in Escherichia coli (E. coli) of amorphadiene, a precursor to the premier antimalarial drug artemisinin.

Using genome-wide transcriptional analysis, the JBEI researchers identified native regions of DNA – called “promoters” – in E. coli that respond to toxic metabolites by promoting the expression of protective genes. They then developed a system based on these promoters for regulating artificial metabolic pathways engineered into the E.coli to enable the bacterium to produce amorphadiene.

“Static regulators of toxic metabolite levels have been developed but this is the first metabolite regulator that responds to changes in microbial growth and environmental conditions,” says Jay Keasling, CEO of JBEI and ranking authority on synthetic biology, who led this research. “Control systems that can sense and respond to environmental or growth changes are needed for the optimal production of a desired chemical.”

Keasling, who also serves as Associate Laboratory Director of Biosciences at Lawrence Berkeley National Laboratory (Berkeley Lab), the lead institute in the JBEI partnership, is the corresponding author of a paper describing this research in the journal Nature Biotechnology. The paper is titled “Engineering dynamic pathway regulation using stress-response promoters.” Co-authors are Robert Dahl, Fuzhong Zhang, Jorge Alonso-Gutierrez, Edward Baidoo, Tanveer Batth, Alyssa  Redding-Johanson, Christopher Petzold, Aindrila Mukhopadhyay, Taek Soon Lee and Paul Adams.

From life-saving drugs, such as artemisinin, to sustainable, green biofuels, the metabolic engineering of microbes for the production of valuable chemicals continues to grow in importance. To date, the most productive microbial hosts have been those engineered with heterologous pathways for which they have little or no native regulation of the metabolites being expressed. However, such unregulated expression of heterologous enzymes can be toxic to the host, which can limit the production of the target chemical to well below levels that could be obtained.

“Although synthetic biology has made great strides in creating novel, dynamic genetic circuits, most control systems for heterologous metabolic pathways still rely on inducible or constitutive promoters,” Keasling says. “Approaches developed to tailor expression strength by means of promoter libraries, mRNA stability or ribosome-binding are optimized for a particular growth phase or condition in the bioreactor, however, growth and environmental conditions change during the fermentation process.”

Since the accumulation of intermediate metabolites to toxic levels in a microbe during a fermentation process can lead to a stress response, Keasling and his JBEI colleagues reasoned that it should be possible to tap a host microbe’s native stress response system when metabolites accumulate. Transcript profiling of the E.coli genome allowed them to evaluate  transcriptional response to a heterologous pathway and create a list of promoters that could be used to respond to intermediate toxicity.

“Using such promoters to regulate pathway expression in response to the toxic intermediate metabolites creates a link between the cell’s metabolic state and the expression of the metabolic pathway,” Keasling says. “This enables us to create biosensors that respond to and regulate pathway intermediates. In silico models have indicated, and we’ve demonstrated in this study that our approach can be used to improve production of a desired chemical over common inducible promoters and constitutive promoters of various strengths.”

Keasling and his colleagues believe their dynamic approach to metabolite regulation could be extended to higher organisms as well, where constitutive promot¬ers are still commonly used. This holds potential for – among other things – improving the accumulation of nutrients in food crops, or decreasing the lignin in energy crops that makes extraction of fuel sugars difficult and expensive.

“What we’re looking at are strategies that could help reduce the problems associated with feeding a larger global population or efficiently converting biomass into renewable fuels,” Keasling says.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,600+ scientific posters on ePosters
  • More Than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Dirty,Crusty Meals Fit for (Long-Dormant) Microbes
Researchers apply the latest analytical techniques to further our understanding of desert biocrusts.
Wednesday, September 23, 2015
Cellular Contamination Pathway for Heavy Elements Identified
Berkeley Lab scientists find that an iron-binding protein can transport actinides into cells.
Tuesday, September 01, 2015
New Mathematics Advances the Frontier of Macromolecular Imaging
Berkeley Lab’s M-TIP solves the reconstruction problem for fluctuation X-ray scattering.
Wednesday, August 12, 2015
Atomic View of Microtubules
Berkeley lab researchers achieve record 3.5 angstroms resolution and visualize action of a major microtubule-regulating protein.
Thursday, August 06, 2015
Unravelling the Mysteries of Carbonic Acid
Researchers have shown how gaseous carbon dioxide molecules are solvated by water to initiate the proton transfer chemistry that produces carbonic acid and bicarbonate.
Thursday, June 18, 2015
Using Microbial Communities to Assess Environmental Contamination
First there were canaries in coal mines, now there are microbes at nuclear waste sites, oil spills and other contaminated environments.
Thursday, May 14, 2015
Bringing Out the Best in X-ray Crystallography Data
“Function follows form” might have been written to describe proteins.
Wednesday, November 06, 2013
Computer Simulations Indicate Calcium Carbonate Has a Dense Liquid Phase
Berkeley Lab research could help scientists predict how carbon is stored underground.
Tuesday, September 24, 2013
New Biochip Holds Great Promise for Quickly Triaging People After Radiation Exposure
Chip could lead to a much-needed way to quickly triage people after possible radiation exposure.
Friday, August 16, 2013
Berkeley Lab Confirms Thirdhand Smoke Causes DNA Damage
A study led by researchers from Lawrence Berkeley National Laboratory has found for the first time that thirdhand smoke causes significant genetic damage in human cells.
Tuesday, June 25, 2013
Sugar for Biofuels: Making Do with More
Joint BioEnergy Institute researchers engineer plant cell walls to boost sugar yields for biofuels.
Tuesday, April 02, 2013
Berkeley Lab’s Advanced Light Source Finds Big Surprise in Paleozoic Scorpion Fossil
Berkeley Lab’s scientists used a powerful microscope to detect remnants of protein and chitin in the exoskeleton of a 417-million-year-old fossil of an extinct mega-scorpion.
Monday, March 07, 2011
The next carbon capture tool could be new, improved grass
Miscanthus, a potential feedstock for biofuel, could pull double duty in the fight against climate change by sequestering carbon in the soil for thousands of years.
Tuesday, October 26, 2010
New Electrostatic-based DNA Microarray Technique Could Revolutionize Medical Diagnostics
Researchers invent a technique in which DNA or RNA assays can be read and evaluated without the need of elaborate chemical labeling or sophisticated instrumentation.
Wednesday, July 02, 2008
Ultraconserved Elements in the Genome: Are They Indispensable?
Three years ago, ultraconserved elements were discovered in the genomes of mice, rats, and humans.
Friday, September 07, 2007
Scientific News
Genetic Defences of Bacteria Don’t Aid Antibiotic Resistance
Genetic responses to the stresses caused by antibiotics don’t help bacteria to evolve a resistance to the medications, according to a new study by Oxford University researchers.
Detecting HIV Diagnostic Antibodies with DNA Nanomachines
New research may revolutionize the slow, cumbersome and expensive process of detecting the antibodies that can help with the diagnosis of infectious and auto-immune diseases such as rheumatoid arthritis and HIV.
Snapshot Turns T Cell Immunology on its Head
New research may have implications for 1 diabetes sufferers.
Tolerant Immune System Increases Cancer Risk
Researchers have found that individuals with high immunoCRIT ratios may have an increased risk of developing certain cancers.
Developing a Gel that Mimics Human Breast for Cancer Research
Scientists at the Universities of Manchester and Nottingham have been funded to develop a gel that will match many of the biological structures of human breast tissue, to advance cancer research and reduce animal testing.
Cell's Waste Disposal System Regulates Body Clock Proteins
New way to identify interacting proteins could identify potential drug targets.
New Approach to Treating Heparin-induced Blood Disorder
A potential treatment for a serious clotting condition that can strike patients who receive heparin to treat or prevent blood clots may lie within reach by elucidating the structure of the protein complex at its root.
Horse Illness Shares Signs of Human Disease
Horses with a rare nerve condition have similar signs of disease as people with conditions such as Alzheimer’s, a study has found.
How a Molecular Motor Untangles Protein
Diseases such as Alzheimer’s, Parkinson’s and prion diseases, all involve “tangled” proteins.
Compound Doubles Up On Cancer Detection
Researchers have found that tagging a pair of markers found almost exclusively on a common brain cancer yields a cancer signal that is both more obvious and more specific to cancer.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos