F. (Francisco) Rosciani

EVOLVE Fellowship - Horizon MSCA COFUND

Reconstructing ancestral cofactor-dependent enzymes

Cofactor-dependent enzymes have evolved to efficiently capture, bind, and utilize specific cofactors for catalysis. In this project, we will employ computational approaches to reconstruct ancestral cofactor-dependent enzymes from specific redox enzyme families. Our primary focus will be on flavin-dependent enzymes, aiming to understand how cofactor specificity and catalysis have evolved over time. In addition to using ancestral sequence reconstruction (ASR) to biochemically characterize ancestral flavoenzymes, we will also perform a comprehensive sequence and structure-based analysis. This dual approach will generate a global overview of the evolutionary pathways of certain redox enzyme families. The insights gained will be used to engineer new cofactor-dependent enzymes with enhanced or novel functionalities.

By integrating these computational methods with experimental validation, we aim to uncover the underlying principles governing enzyme evolution and cofactor-protein interaction. Ultimately, our work seeks to bridge the gap between natural enzyme evolution and the rational design of novel biocatalysts.