A surreal illustration of a protein enzyme with a glowing, flexible core, showcasing the dynamic relationship between structure and function.

Unlocking the Secrets of Enzyme Behavior: How Flexibility Shapes Allostery and Hysteresis

Jordan Keane in Science & Nature September 2025 • 4 min read.

"New research sheds light on the dynamic protein core of UDP-glucose dehydrogenase and its impact on enzyme function and regulation."

Enzymes, the workhorses of biological systems, often exhibit complex regulatory mechanisms beyond simple substrate binding. Allostery, where a molecule binds to a site distinct from the active site to modulate enzyme activity, and hysteresis, where an enzyme's activity depends on its previous state, are two such mechanisms. Understanding these phenomena is crucial for drug development and manipulating metabolic pathways.

UDP-glucose dehydrogenase (UGDH) is a critical enzyme involved in the synthesis of UDP-glucuronic acid, an essential component in drug metabolism. Human UGDH (hUGDH) is regulated by the binding of UDP-xylose, which triggers a conformational change that inhibits the enzyme. This inhibition involves a flexible region within the enzyme known as the allosteric switch, as well as significant repacking of the protein core.

Recent research has focused on how the dynamic nature of hUGDH's protein core contributes to both allostery and hysteresis. By studying a modified version of the enzyme with a less flexible core, scientists have gained insights into the importance of structural adaptability for enzyme regulation.

The Flexible Core: A Key to hUGDH's Regulatory Powers

A surreal illustration of a protein enzyme with a glowing, flexible core, showcasing the dynamic relationship between structure and function.

The allosteric switch in hUGDH is a region that can adopt multiple conformations, influencing the enzyme's activity. The enzyme exists in different states: an active E state, an inactive Eº state, and an intermediate E state. The transition between these states involves not only the allosteric switch but also the surrounding protein core, which provides space for the necessary structural rearrangements.

To investigate the role of core flexibility, researchers created a mutant of hUGDH, named A104L, in which a small cavity within the protein core was filled with a larger amino acid. This substitution was designed to reduce the flexibility of the core and stabilize the E state. The effects of this change were then assessed through a variety of biochemical and structural techniques.

Reduced UDP-Xylose Affinity: The A104L mutant showed a lower affinity for the feedback inhibitor UDP-xylose, indicating that the reduced core flexibility hindered the enzyme's ability to respond to this regulatory signal.
Loss of Cooperativity: Native hUGDH exhibits cooperativity in its response to UDP-xylose, meaning that the binding of one molecule of UDP-xylose enhances the binding of subsequent molecules. The A104L mutant lost this cooperativity, further demonstrating the importance of core flexibility for allosteric regulation.
Abolished Hysteresis: Native hUGDH displays hysteresis, meaning that its activity depends on its previous state. The A104L mutant, however, did not exhibit hysteresis, suggesting that core flexibility is crucial for this behavior.

Structural analysis of the A104L mutant revealed that while the allosteric switch could still adopt different conformations, the overall structure of the protein core was more rigid compared to the native enzyme. This reduced flexibility likely prevented the enzyme from undergoing the structural rearrangements necessary for allosteric regulation and hysteresis.

Implications for Enzyme Function and Drug Design

These findings highlight the importance of protein core flexibility in enzyme regulation. The ability of the protein core to undergo structural rearrangements is crucial for allostery and hysteresis, allowing enzymes to respond dynamically to changing cellular conditions. Understanding these principles can aid in the design of drugs that target specific enzyme conformations or regulatory mechanisms. By modulating protein flexibility, it may be possible to develop novel therapeutic strategies for a variety of diseases.

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This article is based on research published under:

DOI-LINK: 10.1021/acs.biochem.8b00497, Alternate LINK

Title: Hysteresis And Allostery In Human Udp-Glucose Dehydrogenase Require A Flexible Protein Core

Subject: Biochemistry

Journal: Biochemistry

Publisher: American Chemical Society (ACS)

Authors: Nathaniel R. Beattie, Brittany J. Pioso, Andrew M. Sidlo, Nicholas D. Keul, Zachary A. Wood

Published: 2018-11-20

Everything You Need To Know

What is allostery, and why is it important for enzymes?

Allostery is a regulatory mechanism where a molecule binds to an enzyme at a site different from the active site, influencing the enzyme's activity. This is significant because it allows cells to fine-tune enzyme activity in response to changing conditions. The implications of allostery are far-reaching, affecting metabolic pathways and serving as a target for drug development, as modulating allosteric sites can alter enzyme function and overall cellular behavior.

Can you explain what hysteresis means in the context of enzyme activity?

Hysteresis, in the context of enzyme activity, is when an enzyme's current activity is influenced by its past states. This means the enzyme's response to a stimulus depends on its history, not just the immediate conditions. Hysteresis is important because it provides a form of memory, allowing enzymes to maintain a specific activity level even when the initial trigger is removed. The implications of hysteresis are significant in maintaining stable metabolic states and responding to fluctuating environmental signals.

What is UDP-glucose dehydrogenase (UGDH) and what role does it play?

UDP-glucose dehydrogenase (UGDH) is a crucial enzyme that participates in the production of UDP-glucuronic acid. UDP-glucuronic acid is an essential element in drug metabolism. Human UGDH (hUGDH) is specifically regulated by UDP-xylose. This results in a change in the enzyme's shape, which in turn inhibits the enzyme. This process involves a versatile region within the enzyme called the allosteric switch, as well as substantial restructuring of the protein core.

What is the role of the allosteric switch in hUGDH?

The allosteric switch in hUGDH is a region of the enzyme that can adopt multiple conformations. These conformations influence the enzyme's activity by facilitating structural rearrangements within the protein core. The significance of the allosteric switch lies in its ability to act as a control point for enzyme regulation, allowing the enzyme to transition between different states (active, inactive, and intermediate) in response to regulatory signals. The implications are that by understanding and manipulating the allosteric switch, we can potentially control enzyme activity and metabolic pathways.

Why is the flexibility of the protein core important for enzyme regulation?

The flexibility of the protein core in hUGDH is critical for both allostery and hysteresis. It allows the enzyme to undergo the necessary structural rearrangements to respond to regulatory signals, such as the binding of UDP-xylose. When the core is less flexible, as seen in the A104L mutant, the enzyme's ability to respond to these signals is hindered, resulting in reduced UDP-xylose affinity, loss of cooperativity, and abolished hysteresis. The implications are that the dynamic nature of the protein core is essential for the fine-tuned regulation of enzyme activity.