Enzymes are being redesigned to harness light and drive chemical reactions that nature cannot currently perform. The TRIPase project uses genetic code expansion—a technique that inserts artificial building blocks into proteins—to equip enzymes with light-absorbing molecules called photosensitizers. These modified enzymes, or photoenzymes, can then carry out triplet energy transfer reactions, a versatile type of photochemistry that is powerful in organic synthesis but has never been available inside a biocatalyst. This matters because most industrial chemical processes rely on energy-intensive, toxic catalysts. Biocatalysis offers a greener alternative, but natural enzymes cannot perform the excited-state chemistry needed for many valuable transformations, such as cycloadditions or rearrangements. By making these reactions programmable and evolvable inside proteins, TRIPase fills a fundamental gap in synthetic biology. If successful, the project could lead to a new generation of sustainable catalysts that combine the efficiency of natural enzymes with the versatility of photochemistry. This would directly impact pharmaceutical manufacturing, fine chemical synthesis, and materials production—industries where cleaner, more selective processes could reduce waste and energy use. The work is primarily fundamental science, but past advances in directed evolution and photocatalysis have repeatedly led to unexpected industrial and medical breakthroughs.
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The ability to program new modes of catalysis into enzymes would have profound impacts across chemistry and biotechnology, delivering sustainable biocatalytic processes to address societal needs. Genetic code expansion technology opens up exciting new opportunities in biocatalyst design and engineering, by allowing site-selective introduction of new functional elements into proteins as non-canonical amino acid side chains. In TRIPase, I will exploit an expanded genetic code to develop efficient, selective and programmable photoenzymes that operate via triplet energy transfer processes, a versatile mode of reactivity in organic synthesis that is currently not accessible to biocatalysis. These photoenzymes will contain functional elements needed to harness light energy and promote valuable chemical reactions including [2+2] cycloadditions, electrocyclizations, rearrangements and deracemizations. My approach will employ engineered translation components to introduce organic photosensitizers into protein active sites. Protein cavities offer attractive and versatile chiral environments for mediating enantioselective photochemistry, where substrates and key catalytic elements can be accurately positioned within a single pocket. Since the photosensitizers are genetically encoded, active photoenzymes can be optimized via directed evolution to enhance catalytic efficiency and quantum yields, or to impart new functions that are challenging to achieve with small molecule photocatalysts. Structural and biochemical analysis of engineered photoenzymes will shed light on the active site features and mechanistic strategies responsible for enhanced photocatalysis to guide future biocatalyst design. Overall, the platform technology developed in TRIPase will open the door to a wealth of new excited-state chemistry in proteins and in doing so will underpin the development of a new generation of evolvable photocatalysts with efficiencies and specificities akin to natural enzymes.
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