How enzymes actually go about helping to lower the energy of activation needed to start chemical reactions has been the focus of an over 70-year debate. [Sturti/Getty Images]

Enzymes accelerate reactions by helping to lower the activation energy needed to start them. But how enzymes achieve this has been the subject of intense debate.

A research team from Texas and China has investigated the similarities and differences underlying this debate by characterizing catalytic reactions at a detailed molecular level. The scientists published their study (“Key difference between transition state stabilization and ground state destabilization: increasing atomic charge densities before or during enzyme–substrate binding”) in Chemical Science.

The team believes its findings will not only lead to a better understanding of the catalytic power of enzymes, but also to practical drug design applications. They also expect their work to help researchers create artificial enzymes.”

“The origin of the enormous catalytic power of enzymes has been extensively studied through experimental and computational approaches. Although precise mechanisms are still subject to much debate, enzymes are thought to catalyze reactions by stabilizing transition states (TSs) or destabilizing ground states (GSs). By exploring the catalysis of various types of enzyme–substrate noncovalent interactions, we found that catalysis by TS stabilization and the catalysis by GS destabilization share common features by reducing the free energy barriers (DG‡s) of reactions, but are different in attaining the requirement for DG‡ reduction,” wrote the investigators.

“Irrespective of whether enzymes catalyze reactions by TS stabilization or GS destabilization, they reduce DG‡s by enhancing the charge densities of catalytic atoms that experience a reduction in charge density between GSs and TSs. Notably, in TS stabilization, the charge density of catalytic atoms is enhanced prior to enzyme–substrate binding, whereas in GS destabilization, the charge density of catalytic atoms is enhanced during the enzyme–substrate binding.

“Results show that TS stabilization and GS destabilization are not contradictory to each other and are consistent in reducing the DG‡s of reactions. The full mechanism of enzyme catalysis includes the mechanism of reducing DG‡ and the mechanism of enhancing atomic charge densities. Our findings may help resolve the debate between TS stabilization and GS destabilization and assist our understanding of catalysis and the design of artificial enzymes.”

“At present time, two major different reaction mechanisms are proposed to explain enzymatic catalytic power,” said Tor Savidge, PhD, professor of pathology and immunology at the Baylor College of Medicine and the Texas Children’s Microbiome Center. “One proposes that enzymes lower the reaction’s activation energy via stabilization of TS and the other that they do it by destabilizing the GS of enzymes. The current idea is that these mechanisms are mutually exclusive.”

Deliang Chen, PhD, first author at Gannan Normal University in China, and his colleagues took a theoretical approach, taking into consideration previous findings from the Savidge lab showing that the noncovalent interactions of substrates and enzymes with water are important in terms of the mechanism of the enzymatic reactions.

“In a biological environment you have to consider the water—that it is going to interfere with the complex atomic interactions occurring in the enzyme’s active site. We need to consider all of them to understand where exactly you need to have electrostatic interactions that are going to favor that enzymatic process,” continued Savidge. “When you take that into consideration, you can understand how these mechanisms are operating.”

Their analyses led the team to propose something new: that TS and GS are not that different after all. They use a similar atomic mechanism to boost the enzymatic reaction forward. The mechanism involves water in altering the charge of important residues within the catalytic site in a way that favors the formation of an energetically favorable state that drives the enzymatic reaction to occur.

“The important, new point here is not how this is achieved but when it is achieved,” explained Savidge. “We have shown that in stabilization of transition states, the charges that drive the reaction forward are formed before the substrate enters the active site. While in the destabilization ground state this also occurs but after the substrate enters the active site.”

The researchers also proposed that the common mechanism between TS and GS is universal—it can be applied to many enzymatic reactions.

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