Enzymes are the catalytic workhorses of biology, binding molecules together, separating them and reconfiguring them in processes vital for everything from digestion to respiration. Their availability, efficiency, and specificity have long made them popular for reactions outside biological systems, including those involved in food preservation, detergents, and disease diagnosis.
“Enzymes are nature’s preferred catalysts,” said Yang Yang, assistant professor of chemistry at UC Santa Barbara. “They can catalyze reactions with amazing selectivity.” Efforts over the past three decades have also resulted in the development of custom enzymes – enzymes have rapidly evolved for directed purposes, to interact with specific molecules, resulting in a high yield of desired products with unmatched selectivities.
However, Yang added, the reactions that enzymes can enable are relatively limited – a somewhat restricted repertoire for their potent ability to efficiently make products at lower material, energy, and environmental costs.
To bridge this gap and merge the best of both worlds – versatility and selectivity – Yang and his research team have developed a method by which certain enzymes can be made to facilitate useful reactions that have never been seen before in the biological world. , thus expanding their repertoire. and opening up possibilities for processes never before driven by enzymes.
“If we can develop these so-called new to nature enzymatic activities, then we have very powerful biocatalysts for the pharmaceutical and agrochemical industries,” said Yang, who, along with colleagues at UC Santa Barbara and the University of Pittsburgh, is the author of an article published in the journal Science.
Stereochemistry (also known as 3D chemistry) is essential for controlling the bioactivity of small molecule drugs. Most biomacromolecules, including DNAs and proteins, are chiral, which means they have an asymmetric structure.
“It’s like your left hand and your right hand: they look the same but they are not stackable, which means they are chiral,” Yang explained. “To effectively interact with these chiral biomacromolecules, small molecule drugs must be designed with specific stereochemistry. Often, one enantiomer of a chiral drug molecule is very potent, while the other enantiomer is ineffective or even toxic.”
The most efficient way to create such valuable chiral molecules is based on asymmetric catalysis, he said, a process in which a bespoke catalyst selectively produces one enantiomer (non-stackable chiral molecule) instead of another. . Unfortunately, many challenges still exist in the field of asymmetric catalysis. In particular, a widely used class of reactions, namely radical reactions or reactions involving open-shell intermediates, have not yet succumbed to asymmetric catalysis. This problem has long escaped synthetic chemists.
“Organic radicals are very common and extremely active reaction intermediates in synthetic chemistry,” Yang said. “However, we know that controlling the stereochemistry of these reactions is very, very difficult.”
There are two issues that arise, he explained. The first is that the radical, once generated, generally does not interact closely with the catalyst.
“So there is no way to impose stereocontrol on these radical mediated bond formations,” he said.
Second, there is often the trade-off between activity and selectivity.
“If you have a very active species, then it will be relatively difficult for you to control the selectivity of reactions involving these intermediates. So there is usually a trade-off,” Yang said.
The solution? Guided Evolution – Evolving the enzyme to be able to control the radical.
Drawing inspiration from 2018 Nobel Prize-winning Caltech chemical engineer Frances Arnold, who was Yang’s postdoctoral advisor, the team conducted iterative series of cytochrome P450 evolution and screening. The metalloenzyme superfamily is found in all kingdoms of life that contain heme, an iron-containing molecule essential for catalysis.
“Directed evolution uses these cycles of mutation and screening to optimize enzymatic functions,” Yang explained. “In this process, we are creating a huge library of variant enzymes through DNA manipulation.” With a DNA library for target reactions, researchers can express and screen their mutant proteins to help identify promising enzyme catalysts. The improved enzyme then becomes the parent in the next engineering cycle. In this way, through iterative cycles of mutation and screening, optimal enzyme activity and selectivity are achieved.
Using this method, the researchers were able to reuse an enzyme in driving an “unnatural biocatalytic reaction, namely radical cyclization by stereoselective atom transfer”, merging the power of synthetic catalysis and controlling nature. with enzymatic catalysis.
This new ability opens up many possibilities, including a wider variety of molecules on which newly evolved enzymes can act.
“The overall goal is to apply the biocatalysts we are developing to the pharmaceutical and agrochemical industries,” Yang said. “Eventually, with the new tools, we will be able to develop valuable drugs and herbicides that will be useful for our society.”
Researchers access the two enantiomers by varying the reaction time
Qi Zhou et al, radical cyclization of transfer of stereodivergent atoms by modified cytochromes P450, Science (2021). DOI: 10.1126 / science.abk1603
Provided by the University of California – Santa Barbara
Quote: Researchers develop method that gives enzymes the ability to catalyze reactions new to nature (2022, January 6) retrieved January 6, 2022 from https://phys.org/news/2022-01-method- enzymes-ability-catalyze -new-for-nature.html
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