Proefschrift
Evolvability and epistasis studied through the lens of an antibiotic resistance enzyme
Enzymes are innately sensitive to changes in the amino acid sequence, which largely constrains their evolutionary potential, i.e., evolvability. This evolutionary burden can be alleviated in the presence of stabilizing mutations, which increase the buffering capacity of enzymes to tolerate mutations.
- Auteur
- M. Radojković
- Datum
- 12 september 2025
- Links
- Thesis in Leiden Repository
However, since the structure-function relationship of enzymes is based on refined amino acid networks, the effects of mutations in different genetic backgrounds can be highly unpredictable. This phenomenon, known as epistasis, immensely erodes our ability to predict evolution. This thesis explores residue codependency and compensatory potential in enzyme evolution by using the BlaC beta-lactamase from Mycobacterium tuberculosis as a model enzyme. The first line of research focuses on investigating epistasis between pairs of active-site residues in the evolution of inhibitor resistance, while also examining how environmental factors, such as temperature, shape evolutionary outcomes. In the second line of research, it was hypothesized that the introduction of stabilizing mutations would facilitate the evolution of new function by widening the accessible evolutionary landscape. As beta-lactam antibiotics are being re-evaluated for the treatment of tuberculosis, such insights represent invaluable aid in the formulation of clinical drug strategies.