Evolutionary Conservation of Enzymes’ Function Unveiled

A research team led by Professor Nicolas Doucet at the Institut national de la recherche scientifique (INRS) made a significant breakthrough in the field of evolutionary conservation of enzymes’ molecular dynamics. Their research, published in the journal Structure, may assist in developing new therapies to treat serious diseases, such as cancer, or help tackle the growing concern of antibiotic resistance.

Professor Doucet’s team investigated a fundamental issue in macromolecular function research — if a specific protein or enzyme relies on the conformational change of its three-dimensional structure to perform its biological function in humans, do homologous enzymes in other vertebrates or living organisms depend on the same conformational changes? 

The team attempted to answer this question using different enzymes from the same family and analyzed the atomic-scale motions to uncover whether they were preserved throughout evolution. For their work, the scientists undertook molecular and dynamic analyses of several ribonucleases, enzymes known as RNases, that catalyze RNA degradation into smaller elements.

RNases from various vertebrate species, including primates and humans, were selected based on their structural and functional homology. The research shows that RNases that retain specific biological functions in various species also maintain a similar dynamic profile.

In contrast, structurally similar RNases with distinct biological functions have a unique dynamic profile, strongly suggesting that the preservation of dynamics is related to biological processes in these biocatalysts.

Understanding how proteins and enzymes work is vital to developing potential treatments. One way to effectively inhibit an enzyme is by using drugs targeting its active and allosteric sites on the protein surface. This approach aims to disrupt the enzyme’s molecular dynamics while also inhibiting its active site, helping reduce the development of antibiotic resistance.

These findings highlight the importance of understanding molecular dynamics when studying the biological activity of certain enzymes and proteins. Some enzymatic families display unique molecular motions, allowing researchers to develop allosteric inhibitors that don’t affect structurally or functionally homologous enzymes, offering a high degree of selectivity. The study provides an avenue for developing new therapies to treat serious diseases such as cancer and combat antibiotic resistance, two pressing challenges in modern medicine.