Genome mining-driven discovery of enzymes catalyzing stereodivergent transformations

Natural products provide privileged scaffolds for drug discovery, yet their stereochemical complexity often exceeds the limits of synthetic chemistry. Genome mining has emerged as a transformative strategy to uncover cryptic biosynthetic gene clusters and enzymes with noncanonical activities. Recent studies have revealed enzymes exhibiting unusual stereoselectivities, thereby expanding the enzymatic repertoire for constructing complex chiral architectures. Comparative analyses indicated that subtle variations in sequence and active-site environments produce diverse stereochemical outcomes across enzyme families. This review highlights representative examples of stereodivergent enzymes identified through genome- or sequence-guided approaches, emphasizing their substrate scope, catalytic mechanisms, and stereocontrol features. These advances not only deepen our mechanistic understanding of stereoselectivity but also lay the groundwork for rational enzyme engineering and the development of next-generation biocatalysts in pharmaceutical synthesis.