Engineered microbes use light to build new molecules

by Clarence Oxford
Los Angeles CA (SPX) Feb 06, 2026
Researchers are developing new ways to reprogram the cellular machinery of microbes such as yeast and bacteria so they can manufacture useful products for medicine and industry. A team at the Carl R. Woese Institute for Genomic Biology has now shown that they can extend the biosynthetic capabilities of microbes by harnessing light to drive new types of chemical reactions inside cells.

In work published in Nature Catalysis, the researchers demonstrate that the bacterium Escherichia coli can be engineered to produce new-to-nature molecules in vivo using light-driven enzymatic reactions. The study establishes a framework for future advances in the emerging field of photobiocatalysis, which combines light activation with enzyme catalysis to access transformations that are challenging or inaccessible with traditional chemistry or natural enzymes alone.

Photobiocatalysis uses enzymes that only catalyze their target reactions when illuminated. Without light, the enzymes are inactive; with light, they become catalytically competent. Senior author Huimin Zhao, Steven L. Miller Chair of Chemical and Biomolecular Engineering and leader of multiple research themes at the institute, noted that his group has reported several examples in which photocatalysis is merged with enzyme catalysis to create artificial photoenzymes that perform highly selective reactions not seen in nature and that are difficult or sometimes not possible with standard chemical catalysts.

Biomanufacturing relies on microorganisms that naturally excel at synthesizing complex molecules, using enzymes to promote specific reactions in a highly selective way. Because enzymes have strong preferences for particular shapes and sizes of the molecules they transform, they often offer excellent selectivity. However, the palette of reactions accessible to enzymes is much narrower than that of chemical catalysts, which limits the diversity and classes of products that can be produced biologically compared with conventional chemical manufacturing.

The field of photobiocatalysis aims to broaden the reach of biomanufacturing by introducing light-responsive enzymes into cellular metabolism. Although many photoenzymatic reactions have been reported, most cannot easily be integrated into living cells, which is essential for scalable bioprocesses. Earlier work from Zhao's group established proof-of-concept systems for in vitro applications, but those systems needed to be adapted to function efficiently in vivo for practical biomanufacturing.

According to Zhao, the strategy is to embed these engineered photoenzymes directly into cellular metabolic pathways so that whole cells can transform inexpensive feedstocks such as glucose into higher value products. By wiring light-activated steps into metabolism, the cells can be converted into self-contained factories that perform complex synthetic chemistry under mild conditions.

Led by postdoctoral researcher and first author Yujie Yuan, the team built a biosynthetic platform for three classes of carbon-carbon and carbon-nitrogen bond-forming reactions known as hydroalkylations, hydroaminations, and hydroarylations. Using synthetic biology tools, they engineered E. coli to co-produce all of the components required for these light-driven reactions inside the cell, including a set of free radical intermediates that the photoenzymes use to forge new bonds.

A key feature of the platform is that it operates as a fully integrated system without the need to add external radical precursors or other small-molecule reagents. The engineered E. coli strains synthesize the photoenzymes, generate the radical precursors, and supply the substrates in the same cellular environment, allowing the reactions to run using whole cells as the catalytic chassis.

After assembling and optimizing this intracellular system, Yuan and colleagues evaluated its versatility by testing multiple radical precursors. In total, they examined six distinct photoenzymatic reactions and found that the platform was compatible with all six transformations, indicating that the approach can support a range of bond-forming chemistries based on similar radical mechanisms.

To probe scalability, the researchers also carried out scale-up experiments for four of the photoenzymatic reactions in a bioreactor. These tests showed that the engineered cells could perform light-driven synthesis beyond small lab-scale cultures, an essential step toward industrial application, even though performance metrics such as product titers still need improvement.

One of the main challenges the team encountered at larger scale was the relatively low titers, or amounts of desired product, obtained in the bioreactor. Yuan explained that photoenzymatic reactions impose specific process constraints, because they require controlled illumination and often anaerobic conditions, which complicates reactor design and operation.

At present there are no commercial bioreactors designed specifically for light-driven biosynthesis, making it difficult to optimize parameters such as light intensity and distribution inside large vessels. The team is exploring solutions, including discussions with companies about designing custom bioreactors that can accommodate the unique needs of photobiocatalytic processes and provide better data on light exposure.

Looking ahead, the researchers plan to apply their photobiosynthetic platform to the production of high-value molecules, including FDA-approved pharmaceuticals and agricultural chemicals such as herbicides. By enabling microbes to build complex structures that previously required multi-step chemical synthesis, the technology could support more sustainable manufacturing routes for critical products.

Beyond specific applications, the study represents the first example of integrating photoenzymatic reactions directly into cellular metabolism, marking an important milestone for photobiocatalysis. By demonstrating that enzymes with new-to-nature reactivity can be incorporated into living systems to produce compounds that were previously out of reach for biology and, in some cases, even for chemistry, the work opens a promising avenue for expanding the chemical space accessible through microbial manufacturing.

Research Report:Harnessing photoenzymatic reactions for unnatural biosynthesis in microorganisms