Stereochemical Divergence of Polyprenol Phosphate Glycosyltransferases

In the three domains of life, lipid-linked glycans contribute to various cellular processes ranging from protein glycosylation to glycosylphosphatidylinositol anchor biosynthesis to peptidoglycan assembly. In generating many of these glycoconjugates, phosphorylated polyprenol-based lipids are charged with single sugars by polyprenol phosphate glycosyltransferases. The resultant substrates serve as glycosyltransferase donors, complementing the more common nucleoside diphosphate sugars. It had been accepted that these polyprenol phosphate glycosyltransferases acted similarly, given their considerable sequence homology. Recent findings, however, suggest that matters may not be so simple. In this Opinion we propose that the stereochemistry of sugar addition by polyprenol phosphate glycosyltransferases is not conserved across evolution, even though the GT-A fold that characterizes such enzymes is omnipresent. Despite their considerable sequence and structural homology, polyprenol phosphate glycosyltransferases can act with different reaction mechanisms and stereochemical outcomes. In N-linked protein glycosylation, sugars added to polyprenol monophosphate carriers present either the α- or the β-configuration. Novel roles for glycosylated phosphoprenol carriers other than contributing to N-glycosylation have been described.