University of Illinois Urbana-Champaign scientists have successfully hacked the metabolism of common bacteria, teaching Escherichia coli (E. coli) to produce novel molecules using light as a trigger. This proof-of-concept in the emerging field of photobiocatalysis could expand the sustainable manufacturing potential of microbes, allowing them to build chemicals that are currently impossible to make with standard biological or chemical methods.
We often think of microbes like yeast and bacteria as tiny factories, programmed by evolution to make specific biological products. But what if we could reprogram their cellular machinery with new blueprints, using tools not found in nature? Researchers at the Carl R. Woese Institute for Genomic Biology are doing just that, and their latest tool of choice is light. In a study published in Nature Catalysis, the team has for the first time fully integrated light-driven enzymatic reactions into a living microbe’s metabolism, creating a platform for a new type of biosynthesis.
“Photobiocatalysis is basically light-activated catalysis by enzymes. Without light, the target enzyme cannot catalyze a reaction. When light is added, the target enzyme will be activated,” explained the study’s lead researcher, Huimin Zhao, the Steven L. Miller Chair of Chemical and Biomolecular Engineering at UIUC. “These artificial photoenzymes can catalyze selective reactions that cannot be achieved by natural enzymes and are also very difficult, or sometimes even not possible, with chemical catalysis.”
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Traditional biomanufacturing relies on natural enzymes, which are incredibly selective and efficient but limited in the types of chemical transformations they can perform. This constraint caps the variety of products—from drugs to materials—that microbes can sustainably produce. The vision of photobiocatalysis, as reported in Nature Catalysis, is to break this bottleneck by gifting cells with light-responsive enzymes capable of entirely new chemistry.
The challenge, however, has been moving these reactions from a test tube into a living cell. Previous work by Zhao’s group proved the concept in vitro (in glassware), but for scalable manufacturing, the system needs to function in vivo (inside a living cell), using cheap feedstocks like glucose. “Our strategy is to incorporate those photoenzymes in cellular metabolism so that we can use whole cells to convert glucose, which is a very cheap feedstock, to higher value products,” Zhao said.
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Led by postdoctoral researcher Yujie Yuan, the team engineered E. coli to co-produce all necessary components internally: the custom photoenzymes, the target substrate molecules, and a class of highly reactive molecules called free radicals that are crucial for the light-driven reactions. This self-contained system is a key breakthrough. “We don’t need to feed in any radical precursors, and the E. coli can produce the photoenzymes, radical precursors, and the substrates in the whole cells together,” Yuan stated.
The platform was designed for specific, valuable chemical transformations known as hydroalkylations, hydroaminations, and hydroarylations. After optimization, the team put it to the test. “We evaluated six different photoenzymatic reactions, and we found that our platform can be compatible with these reactions,” Yuan said, noting they also successfully scaled up four of the reactions in a bioreactor.
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While promising, the path to industrial application has hurdles. Current product yields, or titers, in larger bioreactors are low. A major complication is the unique need for both light and anaerobic (oxygen-free) conditions during cultivation. “It is a major challenge to determine the conditions in the bioreactor,” Yuan admitted. The team is now exploring solutions, including the potential design of custom bioreactors suited for photobiocatalysis.
Despite these engineering challenges, this study is a foundational leap. It proves that the complex dance of cellular metabolism can be choreographed to include artificial, light-powered steps. This opens a promising avenue for sustainably manufacturing a far wider array of molecules. “This is a proof-of-concept,” Zhao concluded. “It demonstrates it is possible to incorporate engineered enzymes with new-to-nature reactivity into cellular metabolism and produce compounds that cannot be produced by biological approaches or even chemical approaches, at least in the past.”
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