4epimerase

4-epimerase refers to enzymes that catalyze epimerization at the fourth carbon (C-4) of a hexose sugar or its nucleotide-sugar derivative. The reaction converts one sugar isomer into another that is identical except for the configuration at C-4. These enzymes play key roles in carbohydrate metabolism and in the biosynthesis of glycans, often acting on nucleotide- sugar donors such as UDP- or dTDP-sugars.

A well-known example is UDP-glucose 4-epimerase (GalE; EC 5.1.3.2), which interconverts UDP-glucose and UDP-galactose in the Leloir pathway. GalE is typically NAD+-dependent and operates via oxidation at C-4 to a transient 4-keto intermediate, followed by reduction to the alternate configuration; the reaction is reversible and supplies both UDP-glucose and UDP-galactose for glycan assembly. In humans, deficiency of GALE causes galactosemia type 3, illustrating the enzyme’s importance for galactose metabolism and glycoprotein and glycolipid biosynthesis. In bacteria, GalE contributes to the synthesis of cell envelope components such as lipopolysaccharide cores and capsules.

Another class includes dTDP-4-keto-6-deoxy-D-glucose 4-epimerase (RmlC), part of the dTDP-L-rhamnose biosynthesis pathway. RmlC catalyzes the C-4 epimerization of a nucleotide-sugar intermediate to produce dTDP-L-rhamnose, a common bacterial cell-wall constituent. RmlC generally does not require NAD+ and has a distinct catalytic mechanism from NAD+-dependent UDP-glucose 4-epimerases.

4-epimerases are found across bacteria and eukaryotes and are important for glycan diversity and cell-surface structures, making them relevant to both metabolism and potential antimicrobial targeting.