Exploring Enzymes: Unravelling Nature's Catalysts for Sustainable Chemistry
As a professor in Chemical Biotechnology, Dr. Dick B. Janssen has had an impressive scientific track record. One can look for numbers to support this: h index of 88, number of citations, well above 23000 citations and around 50 supervised PhD students.
His interest in enzyme mechanisms grew when his team discovered two different enzymes that hydrolyze a carbon-chlorine bond while studying bacteria growing on dichloroethane. This work was inspired by the emergence of polluted sites dotting the Dutch landscape in the 1980s. Thousands of locations affected by soil and groundwater pollution set the stage for a scientific pursuit. Intrigued by the potential of microbial organisms to counteract these environmental challenges, researchers focused on the world of enzymes.
"We were motivated by the potential of these organisms, and we hoped that some compounds could be removed by biodegradation," recalls Prof. Janssen. "It requires microorganisms that grow on chlorinated compounds, which in turn are dependent on an enzyme cleaving carbon-chlorine bonds, a dehalogenase. Hydrolysis of an alkyl halide by nucleophilic displacement is maybe the first reaction one learns when studying organic chemistry. Yet, it was not described in biology. We first doubted if it could be that simple: no cofactor, no metal, just protein. But careful analysis showed that hydrolysis indeed is the reaction catalyzed by dehalogenases." This curiosity paved the way for the discovery of enzymes that could serve as nature's tools for dismantling pollutants.
In the subsequent decades, Prof. Janssen, together with his research group, turned attention toward the broader potential of enzymes. Inspired by organisms that degrade xenobiotic compounds, they embarked on a quest to unlock the power of enzymes in the realm of synthetic chemistry.
Halohydrin dehalogenase, an enzyme sourced from a bacterium that degrades epichlorohydrin, opened doors to many synthetic possibilities. Again, a simple reaction mechanism, intramolecular nucleophilic displacement, and again, an enzyme from a bacterium that degrades a pollutant. The reverse reaction, epoxide ring opening, has lots of synthetic possibilities since a variety of nucleophiles is accepted. It paves the way for the creation of statin side chains or oxazolidinones and many other intermediates.
Professor Janssen would choose dehalogenases if he had to pick a favourite enzyme. "The advantage of these enzymes lies in their simplicity. This simplicity allows for swift progress and use of various tools, including those derived from structural biology." Collaborations with crystallography experts enabled rapid progress from microbiological scouting via biochemistry and genetics to structure-based engineering, ushering in a new era of applied biocatalysis.
Prof. Janssen's contribution extended beyond academia through collaborations with industry. His work on penicillin acylase exemplifies the benefits of applied biocatalysis. "The idea was to tailor enzymes for beta-lactam antibiotic synthesis," he explains. "This application requires protein engineering since the wild-type enzymes are mainly active as a hydrolase. Successful protein engineering should result in better synthetic performance and straightforward application." It is clear that the industrial use of enzymes has environmental and economic advantages: less use of reagents and solvents, as well as fewer reaction steps, thus, less waste than chemical synthesis and a cheaper production pipeline. And, importantly, the product quality of enzyme-synthesized antibiotics is much better than those synthesized by chemical routes.
In contemplating the future, Professor Janssen focuses on the computational field. "Computational pipelines, with broad applicability, have great potential. We explored some computational tools for enhancing thermostability and controlling selectivity. One would like to be able to query a computational pipeline with a target reaction, or even a product, preferably conditions as well." His vision encompasses a system capable of extracting insights from databases (sequences, structures and literature), applying biophysics-based tools, statistical analyses, and even deep learning." I expect important progress within a decade. It will speed up the development of biocatalytic processes and make project outcomes more predictable and less failure-prone," he concludes.
Link to Prof. Janssen's publication page:
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