Enzymes found in living organisms have impressive catalytic power. Thanks to enzymes, the chemical reactions that sustain life happen millions of times faster than they would without them. Enzymes speed up reactions by helping to lower the activation energy needed to start them, but for more than 70 years, how enzymes accomplish this has been the subject of intense debate.
Dr. Tor Savage, professor of pathology and immunology at Baylor College of Medicine and the Texas Children’s Microbiome Center, and colleagues are changing the way this old argument is made. In his work, published in Chemical sciencethey explored the similarities and differences between the two mechanisms currently under discussion by a detailed characterization of the catalytic reactions at the molecular level.
“Currently, two main different reaction mechanisms have been proposed to explain the catalytic power of the enzyme,” Savage said. “One suggests that enzymes lower the activation energy of a reaction by stabilizing transition states (TS), and the other by destabilizing the enzyme’s ground state (GS). The current idea is that these mechanisms are mutually exclusive.”
The first author, Dr. Deliang Chen of Gangnan Normal University in China, and his colleagues used a theoretical approach, taking into account previous results from the Savage lab showing that non-covalent interactions of substrates and enzymes with water are important in terms of the enzymatic reaction mechanism.
“In a biological environment, you have to consider water – that it will interfere with the very complex atomic interactions that take place in the active site of the enzyme. We have to consider all of them to understand exactly where you need the electrostatic interactions that will facilitate this enzymatic process.” , – said Savage. “If you take that into account, you can understand how these mechanisms work.”
Their analysis led the team to propose something new, that TS and GS are not so different after all. They use a similar atomic mechanism to speed up the enzymatic reaction. The mechanism involves water changing the charge of important residues in the catalytic center in a way that favors the formation of an energetically favorable state that drives the enzymatic reaction.
“The important new point here is not how it is achieved, but when it is achieved,” Savage said. “We have shown that when the transition states are stabilized, the charges that drive the reaction forward are formed before the substrate enters the active site. While in the ground state destabilization also occurs, but after the substrate enters the active site.’
The researchers also suggested that the common mechanism between TS and GS is universal and can be applied to many enzymatic reactions.
“Our findings have important implications not only for a better understanding of the catalytic power of enzymes, but also for the practical application of drug development. “We use our findings to further study microbial enzymatic catalysis in various environments and to design artificial enzymes.”
Yibao Li, Xun Li, Xiaolin Fan from Gannan Normal University, and Xuechuan Hong from Wuhan University School of Pharmacy also contributed to this work.
This work is supported by grants from the National Natural Science Foundation of China (21763002), the Natural Science Foundation of Jiangxi Province (20202ACBL203008), and the National Institute of Allergy and Infectious Diseases (U01-AI24290 and P01-AI152999).
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Materials is provided Baylor College of Medicine. Original written by Ana Maria Rodriguez, Ph.D. Note: Content can be edited for style and length.
