3.A.1.21.2
The Fe³⁺-mycobactin/carboxymycobactin transporter, IrtAB (Rodriguez and Smith, 2006). IrtA contains an FAD-binding domain (Ryndak et al., 2010). M. tuberculosis produces two classes of siderophore, lipid-bound mycobactin and water-soluble carboxymycobactin. Iron-loaded carboxymycobactin is imported into the cytoplasm by IrtAB which has an additional cytoplasmic siderophore interaction domain that may serve as a periplasmic receptor. Membrane-reconstituted IrtAB is sufficient for the import of mycobactins, which are then reduced by the siderophore interaction domain to facilitate iron release (Arnold et al. 2020). Structure determination by X-ray crystallography and cryo-EM not only confirmed that IrtAB has an ABC exporter fold (as indicated by TC-BLAST searches), but also revealed structural peculiarities at the transmembrane region of IrtAB that result in a partially collapsed inward-facing substrate-binding cavity. The siderophore interaction domain is positioned in close proximity to the inner membrane leaflet, enabling the reduction of membrane-inserted mycobactin. Enzymatic ATPase activity and in vivo growth assays revealed that IrtAB has a preference for mycobactin over carboxymycobactin as its substrate (Arnold et al. 2020). The large transporter (Rv1348-1349) of 859 aas seems to have three domains, an extracytoplasmic receptor domain (IrtA), a central membrane domain of 6 TMSs (IrtB) and a C-terminal ATPase (IrtC). If so, there may be two potential receptors (see Mandal et al. 2021 for a review).