Nucleotide sugar epimerases form a very interesting class of enzymes, as they can invert the configuration of a specific hydroxyl group through a single reaction without prior activation or protection steps. As a result, an unusual sugar structure can be generated from a more common counterpart, leading to new properties and potential applications in the food and pharma industries. In many cases, however, the desired combination of regioselectivity (e.g. C2-position) and substrate selectivity (e.g. UDP-Glc) is not present in one and the same enzyme (e.g. to generate UDP-Man), which limits the number of routes that are available for large-scale production processes. In this project, molecular dynamics simulations and ancestral sequence reconstruction will be used to gain a better understanding of the structure-function relationships operative in these enzymes. Based on that information, we will design a UDP-Glc 2-epimerase by combining features of UDP-Glc 4-epimerase and CDP-Tyv 2-epimerase. Ultimately, it should become possible to design new, tailor-made biocatalysts for the synthesis of virtually all rare sugars and derivatives thereof.