Unveiling the hidden world of enzymes: A gateway to advancements in health and drug development

Earlier this year, Professor Nicolas Doucet and his team at Institut national de la recherche scientifique (INRS) achieved a significant breakthrough in the field of evolutionary conservation of molecular dynamics in enzymes. Their groundbreaking research, published in the journal Structure, suggests potential applications in healthcare, including the development of novel drugs for the treatment of serious diseases like cancer and combating antibiotic resistance.

Professor Doucet, an expert in protein dynamics, is fascinated by the hidden intricacies that are essential to all forms of life but remain imperceptible to the naked eye. His research focuses on proteins and enzymes, exploring the enigmatic connections between their structure, function, and atomic-level motion.

To explore uncharted territories in this minuscule realm that still holds many secrets, Professor Doucet approaches problems from a conceptual standpoint. He recognizes that a touch of imagination can illuminate numerous avenues for investigation, even in a domain that we still understand relatively little about. Nevertheless, he emphasizes the meticulous nature of the scientific process.

“As we delve into this minute world, which is brimming with mysteries, yet fundamental to life, a dash of imagination can help us envisage diverse pathways for exploration. However, the scientific process requires utmost precision,” explained Professor Doucet, who conducts research at the Armand-Frappier Santé Biotechnologie Research Centre and serves as the scientific co-head of the Nuclear Magnetic Resonance Spectroscopy Lab at INRS.

Towards a better understanding of macromolecular function

One of the key questions explored by Professor Doucet’s team in their study was a fundamental issue in the field. They aimed to investigate whether the conformational changes in the three-dimensional structure of a specific protein or enzyme, crucial for its biological function in humans, are also reliant on these same changes in homologous enzymes found in other vertebrates or organisms.

In simpler terms, they wanted to understand if the essential motions required for the biological function of proteins and enzymes are selected and conserved as a molecular evolutionary mechanism across all forms of life.

Despite the limited knowledge surrounding the intricate workings of these life-sustaining macromolecules, the team embarked on finding answers to this question.

Advancements in biochemical and biophysical technologies in recent decades have facilitated the observation of molecular structures of proteins and enzymes with greater ease.

“Our approach involved studying various enzymes from the same family to analyze multiple proteins that perform the same biological function. We compared their atomic-scale motions to uncover whether these motions are preserved throughout evolution. Surprisingly, despite overall similarities between species, we discovered that the movements diverge instead,” elucidated David Bernard, the lead author of the study. Bernard was a Ph.D. student in Professor Doucet’s lab at INRS during the research and currently serves as a researcher at NMX.

Molecular motions of great importance

The biological function of proteins and enzymes depends not only on their amino acid sequence but also on their three-dimensional structure. In recent years, scientists have discovered a close connection between protein dynamics and the biological activity of certain enzymes and proteins.

If a given enzyme exhibits such dependence on protein dynamics, the question arises: are these motions conserved from an evolutionary perspective? In other words, do specific atomic motions within an enzyme family persist and remain conserved to maintain biological function?

If so, it would imply that the preservation of atomic-scale motions in proteins is crucial for the selective pressure required to uphold their biological function, similar to the preservation of amino acid sequences or protein structures.

In their article, Professor Doucet’s team, in collaboration with researchers from the United States, presents a molecular and dynamic analysis of several ribonucleases (RNases). RNases are enzymes responsible for breaking down RNA into smaller components. The study focused on RNases from various vertebrate species, including humans and primates, chosen based on their structural and functional similarities.

Building upon their previous research, the team convincingly demonstrates that RNases with shared biological functions across different species also exhibit highly similar dynamic profiles. Conversely, RNases with similar structures but distinct biological functions demonstrate unique dynamic profiles. This strongly suggests that the conservation of dynamics is linked to the biological function of these biocatalysts.

Understanding the essential motions for the function of proteins and enzymes holds promise for leveraging their therapeutic potential. It opens up possibilities for targeting these motions to modulate or inhibit protein and enzyme functions within cells, known as allosteric modulation or inhibition.

For instance, by successfully inhibiting an enzyme through drug binding at its active (orthosteric) site while simultaneously targeting an allosteric site on the protein’s surface, researchers can achieve dual benefits. This strategy involves inhibiting the enzyme’s active site while also disrupting its molecular dynamics through allosteric targeting. Such inhibitory action can significantly reduce the development of antibiotic resistance, addressing the pressing global health issue of drug resistance.

In summary, the unique observation of specific molecular motions within certain enzyme families enables researchers to achieve a remarkable level of selectivity in developing allosteric inhibitors without affecting structurally or functionally homologous enzymes.

These findings have been published in the journal Structure.

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