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A folded substrate can slow down an enzymatic reaction

SEP 05, 2025
Researchers discovered the important role of a substrate’s shape in its breakdown.
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DOI: 10.1063/10.0039304

A folded substrate can slow down an enzymatic reaction internal name

A folded substrate can slow down an enzymatic reaction lead image

Breaking down proteins, a process known as proteolysis, is critical for digestion and recycling of amino acids. Enzymes are the key component in this process, as they break down substrates — the proteins — so they can be used by the body. While substantial research has focused on the effects of the enzyme’s conformation on the efficiency of the reaction, the substrate’s role is less well understood.

Das et al. studied the proteolysis of human serum albumin (HSA) to determine how its folding state can affect the reaction efficiency.

“Our key finding is that the proteolysis rate strongly depends on the substrate’s conformational state,” said author Pratik Sen.

HSA is a protein with three well-defined conformational states, while the enzyme, papain, is robust enough to withstand the harsh environments necessary for testing without undergoing significant changes in shape or activity.

Using fluorescently labeled HSA, the researchers could track the large substrate’s digestion over an extended time, giving them more data than a smaller substrate could.

The researchers found that proteolysis was significantly slowed when the HSA took on a compact shape, but when the HSA was mostly unfolded, it allowed better access to its cleavage site, increasing the reaction rate.

In the future, the researchers plan to study other substrate-enzyme pairings to generalize their findings.

“We also intend to develop a mathematical model of proteolysis that quantitatively incorporates substrate conformation,” Sen said. “This study could have broader implications across various fields, such as proteome workflows, where digestion efficiency may be influenced not only by enzyme conditions but also by the subtle structural states of protein targets.”

Source: “Dissecting the role of substrate folding in enzymatic digestion,” by Nilimesh Das, Tanmoy Khan, Soumya Chaudhury, Bhaswati Sengupta, and Pratik Sen, Biointerphases (2025). The article can be accessed at https://doi.org/10.1116/6.0004803 .

This paper is part of the Biointerfaces in India Collection, learn more here .

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