UDP-hexose 4-epimerases: a view on structure, mechanism and substrate specificity

• GalEs display unusual enzymologic, chemical, and stereochemical properties.
• UDP-sugar 4-epimerases are important in Leloir and polysaccharide synthesis pathways.
• GalEs can be active on a broad range of UDP-sugars and derivatives.
• Understanding of human GalE important for type III galactosemia treatment.
• New insights could lead to drug and vaccine design and antibiotic development.

UDP-sugar 4-epimerase (GalE) belongs to the short-chain dehydrogenase/reductase (SDR) superfamily of proteins and is one of enzymes in the Leloir pathway. They have been shown to be important virulence factors in a number of Gram-negative pathogens and to be involved in the biosynthesis of different polysaccharide structures. The metabolic disease type III galactosemia is caused by detrimental mutations in the human GalE. GalE and related enzymes display unusual enzymologic, chemical, and stereochemical properties; including irreversible binding of the cofactor NAD and uridine nucleotide-induced activation of this cofactor. These epimerases have been found active on UDP-hexoses, the N-acetylated and uronic acid forms thereof as well as UDP-pentoses. As they are involved in different pathways and functions, a deeper understanding of the enzymes, and their substrate promiscuity and/or selectivity, could lead to drug and vaccine design as well as antibiotic and probiotic development. This review summarizes the research performed on UDP-sugar 4-epimerases’ structure, mechanism and substrate promiscuity.

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