Arabinosyltransferase EmbB (EmbB) and Arabinosyltransferase EmbC (EmbC) (EmbB/C)

Arabinosyltransferases EmbB and EmbC are essential membrane-bound enzymes in Mycobacterium tuberculosis responsible for the synthesis of critical cell wall components (Zhang et al., 2020, Science). EmbB is primarily involved in the polymerization of the arabinan domain of arabinogalactan, which links the peptidoglycan layer to the outer mycolic acids, while EmbC is dedicated to the synthesis of lipoarabinomannan, a key lipoglycan involved in host-pathogen interactions (Goude et al., 2009, Journal of Bacteriology). These enzymes utilize decaprenyl-phospho-arabinose (DPA) as a sugar donor to build the complex branched arabinan structures necessary for mycobacterial viability and virulence (Belanger et al., 1996, PNAS). As the primary targets of the first-line antitubercular drug ethambutol, these enzymes are central to tuberculosis therapy. Ethambutol inhibits their activity by mimicking the substrate DPA, thereby disrupting cell wall assembly and leading to bacterial lysis (Zhang et al., 2020, Science). Mutations in the genes encoding these enzymes, particularly in the embB gene at position 306, are major drivers of clinical resistance to ethambutol (Telenti et al., 1997, Nature Medicine). Understanding the structural biology of the EmbB/C complexes is vital for developing next-generation inhibitors that can overcome existing resistance mechanisms.

Other names

EmbBEmbCArabinosyltransferase BArabinosyltransferase CEthambutol-sensitive arabinosyltransferase

Ethambutol acts as an antimetabolite that competes with the substrate decaprenyl-phospho-arabinose (DPA) for binding to the active site of the arabinosyltransferases EmbB and EmbC. This inhibition prevents the polymerization of arabinose into the arabinogalactan and lipoarabinomannan layers of the mycobacterial cell wall, leading to increased cell wall permeability and bacterial death.