Visible‑light photoenzymes craft drug‑relevant β‑lactams and cyclobutanes in ordinary air

Scientists have engineered molecular catalysts that harvest readily available blue LED light (405 nm) to stitch together four‑membered ring structures, such as β‑lactams, the core of many antibiotics, and cyclobutanes, common components in agrochemicals, while working openly in air. One of the photoenzymes (VEnT1.3) achieved turnover numbers exceeding 1,300, while another (SpEnT1.3) demonstrated over 300 turnovers, with both achieving enantiomeric excess up to 99% for their respective reactions. The research could point to a practical, more energy-efficient route for making chiral building blocks.

The research, published in Nature Chemistry, aims to overcome the challenges inherent in developing [2 + 2] cyclases with benzophenone triplet sensitizers. As the authors note in the abstract, the properties of benzophenone requires using ultraviolet light while also “limit[ing] photochemical efficiency and restrict[ing] the range of chemistries accessible.” To sidestep those hurdles, they engineered an orthogonal Methanococcus jannaschii tyrosyl-tRNA synthetase/tRNA pair to encode thioxanthone triplet sensitizers into proteins.

At the violet edge of the visible spectrum, 405 nm borders on ultraviolet (UV-A) and is often classified as “near-UV” or described as the “UV/visible radiation boundary region.” 405 nm LEDs are widely available, used in everything from 3D printing, dental curing, fluorescence microscopy, and as an excitation source in spectroscopy. Unlike earlier UV-driven systems, these catalysts operate in open air without requiring gloveboxes or higher energy input.

The superior light-handling capabilities of the thioxanthone sensitizer are key to the enzymes’ success. Because thioxanthone efficiently absorbs visible light, these engineered photoenzymes can work quickly and perform their chemical task many times over (high catalytic rates and turnover numbers). For example, one of these enzymes, VEnT1.3, rapidly drives a specific ring-forming reaction ([2+2] cycloaddition) at a speed (k_cat) of about 13 reactions per second. Another enzyme, SpEnT1.3, demonstrates precision by selectively creating complex, antibiotic-like ring structures (spirocyclic β-lactams from quinolone substrates), achieving up to 99% purity of one desired mirror-image form (enantiomeric excess) and a 22:1 preference for a specific spatial arrangement (diastereomeric ratio). This level of precise control over the highly reactive molecules formed during the light-driven process “suppresses a competing substrate decomposition pathway observed with small-molecule sensitizers, underscoring the ability of engineered enzymes to control the fate of excited-state intermediates,” as the abstract for the paper notes. That is a common hurdle when using light-sensitizers that aren’t neatly packaged inside an enzyme.

These reactions occur within a standard phosphate buffer solution at 4°C. The performance levels meet or even surpass the typical operational thresholds required for continuous-flow photoreactors often used in the manufacture of Active Pharmaceutical Ingredients (APIs).

By overcoming the limitations of traditional UV-driven methods, which often suffer from lower photochemical efficiency and require more specialized conditions, these enzyme-driven reactions offer a pathway to reduce both initial investment costs and overall energy consumption. The researchers suggest in the Nature Chemistry article that this thioxanthone-based light-activation strategy should transfer to other enzyme structures, as this system “enables the development of highly efficient and oxygen-tolerant photoenzymes that are powered by visible light and can achieve selective conversions that are beyond the reach of existing photocatalysts.”