Plasticity of enzyme active sites

Area of Science:

• Biochemistry and Molecular Biology
• Enzymology
• Evolutionary Biology

Background:

• Enzyme homologues typically share reaction chemistry via conserved functional groups.
• However, enzyme active sites exhibit flexibility, with unconserved residues mediating similar catalytic functions.
• This active site plasticity challenges traditional views of evolutionary conservation in enzyme catalysis.

Purpose of the Study:

• To explore the evolutionary mechanisms underlying the observed flexibility and variability in enzyme active sites.
• To investigate how different functional groups can fulfill equivalent mechanistic roles across diverse enzyme families.
• To understand the implications of active site plasticity for enzyme evolution and functional convergence.

Main Methods:

• Comparative analysis of enzyme active site structures and sequences.
• Bioinformatic approaches to identify conserved and unconserved functional groups.
• Phylogenetic analysis to trace the evolutionary history of catalytic residues and active site locations.

Main Results:

• Demonstrated that functionally equivalent catalytic roles can be mediated by spatially distinct and unconserved residues.
• Identified instances where catalytic atoms maintain spatial equivalence despite sequence divergence.
• Observed cases of complete active site relocation within the protein scaffold.

Conclusions:

• Enzyme active site variability is a significant evolutionary phenomenon.
• Potential evolutionary drivers include functional group mobility, independent specialization, functional convergence, and circular permutation.
• Understanding active site plasticity is crucial for deciphering enzyme evolution and designing novel biocatalysts.