Diverse functions for acyltransferase-3 proteins in the modification of bacterial cell surfaces

Abstract

The acylation of sugars, most commonly via acetylation, is a widely used mechanism in bacteria that uses a simple chemical modification to confer useful traits. For structures like lipopolysaccharide, capsule and peptidoglycan, that function outside of the cytoplasm, their acylation during export or post-synthesis requires transport of an activated acyl group across the membrane. In bacteria this function is most commonly linked to a family of integral membrane proteins - acyltransferase-3 (AT3). Numerous studies examining production of diverse extracytoplasmic sugar-containing structures have identified roles for these proteins in O-acylation. Many of the phenotypes conferred by the action of AT3 proteins influence host colonisation and environmental survival, as well as controlling the properties of biotechnologically important polysaccharides and the modification of antibiotics and antitumour drugs by Actinobacteria. Herein we present the first systematic review, to our knowledge, of the functions of bacterial AT3 proteins, revealing an important protein family involved in a plethora of systems of importance to bacterial function that is still relatively poorly understood at the mechanistic level. By defining and comparing this set of functions we draw out common themes in the structure and mechanism of this fascinating family of membrane-bound enzymes, which, due to their role in host colonisation in many pathogens, could offer novel targets for the development of antimicrobials.

Keywords: O-acetylation; O-succinylation; acetyl-CoA; antibiotics; capsule; exopolysaccharide; lipopolysaccharide; membrane-bound acyltransferase; mycolic acid; nodulation.

Fig. 1.

(a) Acyl modifications known to be added to sugars by AT3 proteins mentioned in this review. Note that only some modifications alter the charge of the sugar. (b) Chematic model of OafB adapted from [11]. The known structure of the OafB SGNH domain (PDB:6SE1) (grey) is shown oriented via TMH11 and the periplasmic linking region (orange) and the AT3 (purple). Positions of residues known to be essential for function are indicated by white stars. Yellow stars represent the acyl-group being transferred to the O-antigen on the outer leaflet of the inner membrane.

Fig. 2.

Schematic diagram representing the functional diversity of different targets for O-acylation by AT3 proteins, their domain structures and acyl donors that have been experimentally demonstrated to be used by each enzyme.