A team of Rensselaer researchers led by metabolic engineer Mattheos Koffas has developed a technique to more efficiently produce large quantities of the fatty acids that form the basis of compounds used in biofuels, medicine, and commodity chemical production.

Results of the study conducted by Koffas and his research group in the Center for Biotechnology and Interdisciplinary Studies over the past two years are detailed in a paper called “Improving fatty acids production by engineering dynamic pathway regulation and metabolic control,” which was published by the Proceedings of the National Academy of Sciences. The research was supported by the National Science Foundation.

Mattheos Koffas

Mattheos Koffas

Koffas and his team developed a sensor that manipulates in real time two cellular pathways that regulate production of malonyl-CoA, which is the limiting precursor in fatty acid production. By utilizing the sensor-based dynamic regulation technique at the cellular level, the researchers were able to maximize production of malonyl-CoA while minimizing damage to the cell.

The fatty acids produced by this technique are essentially identical to those produced naturally by plants and microorganisms and are used as the basis of biofuels and chemical compounds used in medicine and industry. “In order for these fatty acids to be used in biofuel, for example, we need techniques to produce them inexpensively and in huge quantities,” Koffas said.

Previous efforts to produce fatty acids relied on static regulation—turning genes on or off entirely—rather than dynamic regulation.

“We have basically developed a sensor that can sense the state of the cell and, based on the state of the cell, can decide which genes need to be ‘upregulated,’ so we increase their transcription, and which genes need to be ‘downregulated,’ so we turn down their transcription levels,” Koffas said.

Koffas’ team created the sensor by harnessing two promoters that behave in opposite manners within the cell and combining their behaviors to create a “switch.” One of the promoters turns off malonyl-CoA biosynthesis when it senses a build-up in the cell, the other turns on malonyl-CoA production when it senses a scarcity in the cell.

“The switch controls both the sink pathway and the source pathway simultaneously to control how much malonyl-CoA is produced,” Koffas said. “This dynamic regulation opens up new venues to optimize production of malonyl-CoA-derived compounds.”

The concept of a sensor that controls cellular chemical production has implications beyond fatty acids. “Potentially this sensor can be used for improving yields for other chemicals of commercial interest,” Koffas said.

Koffas is the Career Development Associate Professor in the Department of Chemical and Biological Engineering. He was joined in this research by research associate professor Fuming Zhang, research assistant professor Linguyn Li, graduate student Peng Xu, and Gregory Stephanopoulos, a chemical engineering professor at the Massachusetts Institute of Technology.