The Glycosyltransferases of LPS Core: A Review of Four Heptosyltransferase Enzymes in Context

Abstract

Bacterial antibiotic resistance is a rapidly expanding problem in the world today. Functionalization of the outer membrane of Gram-negative bacteria provides protection from extracellular antimicrobials, and serves as an innate resistance mechanism. Lipopolysaccharides (LPS) are a major cell-surface component of Gram-negative bacteria that contribute to protecting the bacterium from extracellular threats. LPS is biosynthesized by the sequential addition of sugar moieties by a number of glycosyltransferases (GTs). Heptosyltransferases catalyze the addition of multiple heptose sugars to form the core region of LPS; there are at most four heptosyltransferases found in all Gram-negative bacteria. The most studied of the four is HepI. Cells deficient in HepI display a truncated LPS on their cell surface, causing them to be more susceptible to hydrophobic antibiotics. HepI–IV are all structurally similar members of the GT-B structural family, a class of enzymes that have been found to be highly dynamic. Understanding conformational changes of heptosyltransferases are important to efficiently inhibiting them, but also contributing to the understanding of all GT-B enzymes. Finding new and smarter methods to inhibit bacterial growth is crucial, and the Heptosyltransferases may provide an important model for how to inhibit many GT-B enzymes.

Leloir Glycosyltransferases in Applied Biocatalysis: A Multidisciplinary Approach

“…The high glycosylation efficiency with Leloir GTs arises from a favorable thermodynamic equilibrium K eq in these examples, determined by the sugar nucleotide donor and carbohydrate or aglycone acceptor, pH, and ionic strength. As mentioned earlier, in a few examples the hydrolysis of the NDP-sugar donor has been reported for Leloir GTs [70,71,72,73,74,75,76,77]. In these particular cases, it is important to emphasize that the glycosylation with Leloir GTs is under kinetic control, and the sugar acceptor and water are competing nucleophiles throughout the entire course of reaction [70,71,72,73,74,75,76,77].…”

“…The exclusion of hydrolysis activity of the nucleotide sugar donor separates glycoside hydrolases from glycosyltransferases. Nevertheless, hydrolysis of the nucleotide sugar donor in the absence of a sugar acceptor has been reported and is referred to as “error hydrolysis” [70,71,72,73]. Hence, the competition between water or a sugar acceptor as nucleophile is important for the efficiency of glycosylation.…”

Comparison of the TLR4/NFκB and NLRP3 signalling pathways in major organs of the mouse after intravenous injection of lipopolysaccharide

“…Lipopolysaccharides (LPS) is a mucopolysaccharide produced by Gram-negative bacteria (Rosner et al. 1979; Cote and Taylor 2017). LPS is also a major factor that causes cell damage during the bacterial invasion of the body.…”

Beyond the A‐layer: adsorption of lipopolysaccharides and characterization of bacteriophage‐insensitive mutants of Aeromonas salmonicida subsp. salmonicida

“…Indeed, this enzyme family catalyzes the addition of multiple heptose sugars to form the core region of LPS. Cells deficient in HepI, the most studied heptosyltransferase in Gram‐negative bacteria, display a truncated LPS on their cell surface (Cote and Taylor, ). In the present case, the mutation clearly causes a truncated LPS (Fig.…”