Rebuilt ancestral enzyme reveals pathway of functional diversification in bacteria

Scientists have successfully reconstructed a centuries‑old bacterial protein, offering fresh insight into how closely related enzymes evolve distinct biochemical roles. The work, conducted by a collaborative team from Kiel University, the DESY research center and the Center for Structural Systems Biology, demonstrates that subtle changes in protein structure can drive major functional shifts.

Using ancestral sequence reconstruction techniques, the researchers inferred the genetic blueprint of an early version of a common bacterial enzyme. They then expressed the protein in the lab and determined its three‑dimensional structure with high‑resolution X‑ray crystallography at DESY’s synchrotron facilities. By comparing the ancient structure to those of modern relatives, the team traced the stepwise modifications that gave rise to specialized activities.

The analysis revealed that the primordial enzyme retained the core scaffold shared by its descendants but lacked the specialized active‑site residues that confer the diverse functions seen today. Introducing a handful of mutations into the ancient protein recreated the catalytic properties of several modern variants, underscoring how incremental alterations can generate new enzymatic capabilities.

These findings have practical implications for fields ranging from antibiotic development to industrial biotechnology. Understanding the molecular routes by which bacterial enzymes diversify can help predict how pathogens might evolve resistance mechanisms, and it offers a template for engineering novel catalysts with tailored functions.

Protein evolution has long been a central puzzle in molecular biology, especially because the intermediate forms that link ancient and modern proteins are rarely preserved. Ancestral reconstruction provides a rare glimpse into these lost stages, allowing scientists to test evolutionary hypotheses in the laboratory rather than relying solely on computational models.

Lead investigator Holger Sondermann, a professor at Kiel University and head of the Structural Systems Biology program, noted that the approach can be extended to other enzyme families. Future studies aim to map evolutionary trajectories across a broader spectrum of bacterial proteins, potentially guiding the design of synthetic enzymes for medical and environmental applications.