UCLA researchers led by Professor Soumitra Athavale have taught enzymes an entirely new reaction mechanism—a radical hydrogenation process that nature itself never discovered.
Hydrogenation — the process of adding hydrogen atoms to carbon–carbon double bonds — is one of the cornerstones of modern chemistry, enabling the synthesis of everything from medicines and fragrances to fuels and polymers. For over a century, these reactions have been driven by precious metal catalysts such as platinum, palladium, rhodium, or iridium—effective but costly, energy-intensive, and environmentally burdensome.
Nature, by contrast, performs hydrogenation through a completely different logic. Biological enzymes use “hydride” chemistry—transferring negatively charged hydrogen equivalents from cofactors like NADH—to reduce certain polarized, electron-poor bonds. But this strategy fails for the vast majority of alkenes, especially unactivated alkenes, the simple, non-polar double bonds that make up most industrial feedstocks and drug molecules. Despite biology’s ingenuity, it has never evolved a way to hydrogenate these challenging targets.
A team at UCLA led by Soumitra Athavale, has now broken this natural barrier. The researchers have taught enzymes an entirely new reaction mechanism—a radical hydrogenation process that nature itself never discovered. Their paper, titled ‘Biocatalytic, Asymmetric Radical Hydrogenation of Unactivated Alkenes,’ was recently published in the journal Science. The team was led by postdoctoral researchers Drs. Jaicy Vallapurackal and Rajib Mandal. Co-authors are graduate students Justin Bossenbroek, Aris V. Rubio, Ethan Poladian, James D. Collings, Cesar Torres, Julian Morales, Max B. Lyons, and Kyle Schultz, Masters student Matthew Hendrickson, and Professors Hannah S. Shafaat and Ken Houk.
In this strategy, nicknamed BioHAT (biocatalytic cooperative metal hydrogen atom transfer), an iron-containing enzyme activates a simple silane and delivers hydrogen atoms separately and asymmetrically to the double bond. One hydrogen comes from the metal center, the other from a nearby cysteine amino acid. This unusual “split-source” mechanism mirrors cutting-edge synthetic chemistry but has now been encoded directly into a protein scaffold—a first in biochemistry.
Evolving New Enzymes from Scratch
Using directed evolution Athavale’s team screened and iteratively mutated hundreds of enzyme variants to find versions that could carry out this reaction efficiently and selectively. Within just a few rounds, they created compact, robust protoglobin-based enzymes capable of asymmetric hydrogenation under air, at room temperature, in water, and on gram scales. The new biocatalysts use earth-abundant iron instead of rare precious metals, avoid pressurized hydrogen gas, and operate in environmentally benign solvents. Remarkably, they achieve precise control of molecular handedness (chirality)—a key requirement for pharmaceuticals—by shaping the enzyme’s active site to steer each hydrogen atom to the correct face of the double bond. The same logic even allows for custom isotopic labeling with deuterium, enabling applications in drug metabolism and imaging.
The work represents a paradigm shift in how enzymes can manipulate chemical bonds. For the first time, a protein catalyst performs an asymmetric hydrogenation through a stepwise radical mechanism, expanding the playbook of biological catalysis beyond the constraints of classical “hydride transfer.”
“Nature has spent billions of years perfecting one way of doing hydrogenation,” Athavale said. “We’ve shown that with the right design and evolution, enzymes can be re-taught to use a completely different—and far more versatile—mechanism. We believe that this process will provide solutions to longstanding challenges in one of the most important reactions in organic chemistry – asymmetric alkene hydrogenation”
Implications for the Future
This breakthrough opens the door to a new generation of sustainable catalytic technologies, bridging the precision of biology with the power of radical chemistry. Because the required mutations are simple to encode in DNA, the approach could be generalized across hundreds of natural heme proteins to tailor catalysts for diverse industrial transformations.
In essence, the study shows that genetically encoded enzymes can now rival and in some cases surpass precious-metal catalysts, paving the way for greener pharmaceuticals, fine chemicals, and materials made entirely through biocatalytic routes. It also demonstrates a new fundamental approach to how precise geometric control can be achieved in challenging hydrogen atom transfer reactions.
Athavale joined the UCLA faculty as an Assistant Professor in 2023. In 2024, he was appointed the inaugural John D. and Edith M. Roberts Term Chair in Organic Chemistry. The Athavale group focuses on synthetic organic chemistry, biomolecular evolution, and chemical biology, researching synthetic chemistry and biocatalysis, the organic chemistry of evolution, fundamental enzyme structure-function relationships, and engineered enzymes as next-generation co-therapeutics.
For more information about the research, contact Professor Soumitra Athavale, athavale@g.ucla.edu.
Penny Jennings, UCLA Department of Chemistry & Biochemistry, penjen@g.ucla.edu.
